Certain chemical entities, compositions, and methods

ABSTRACT

Chemical entities that are kinase inhibitors, pharmaceutical compositions and methods of treatment of cancer are described.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application Ser.No. 61/725,033, filed on Nov. 12, 2012, which application isincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

There are at least 400 enzymes identified as protein kinases. Theseenzymes catalyze the phosphorylation of target protein substrates. Thephosphorylation is usually a transfer reaction of a phosphate group fromATP to the protein substrate. The specific structure in the targetsubstrate to which the phosphate is transferred is a tyrosine, serine orthreonine residue. Since these amino acid residues are the targetstructures for the phosphoryl transfer, these protein kinase enzymes arecommonly referred to as tyrosine kinases or serine/threonine kinases.

The phosphorylation reactions, and counteracting phosphatase reactions,at the tyrosine, serine and threonine residues are involved in countlesscellular processes that underlie responses to diverse intracellularsignals (typically mediated through cellular receptors), regulation ofcellular functions, and activation or deactivation of cellularprocesses. A cascade of protein kinases often participate inintracellular signal transduction and are necessary for the realizationof these cellular processes. Because of their ubiquity in theseprocesses, the protein kinases can be found as an integral part of theplasma membrane or as cytoplasmic enzymes or localized in the nucleus,often as components of enzyme complexes. In many instances, theseprotein kinases are an essential element of enzyme and structuralprotein complexes that determine where and when a cellular processoccurs within a cell.

The identification of effective small compounds which specificallyinhibit signal transduction and cellular proliferation by modulating theactivity of tyrosine and serine/threonine kinases to regulate andmodulate abnormal or inappropriate cell proliferation, differentiation,or metabolism is therefore desirable. In particular, the identificationof compounds that specifically inhibit the function of a kinase which isessential for processes leading to cancer would be beneficial.

SUMMARY OF THE INVENTION

In one aspect, provided is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₁₀ are independently hydrogen,cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl,sulfonyl, optionally substituted alkoxy, optionally substitutedcycloalkyloxy, optionally substituted aryloxy, optionally substitutedheteroaryloxy, optionally substituted heterocycloalkyloxy, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocycloalkyl, optionally substituted amino, optionallysubstituted acyl, optionally substituted alkoxycarbonyl, optionallysubstituted aminocarbonyl, optionally substituted aminosulfonyl,optionally substituted carbamimidoyl, or optionally substituted alkynyl;

R₉ is hydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; and

R₁₁ is hydroxyl, formyl, optionally substituted alkoxy, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(NR₁₄)NR₁₂R₁₃,—C(NCN)NR₁₂R₁₃, or —SO₂NR₁₂R₁₃, where R₁₂ is optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; and R₁₃ and R₁₄ are independently hydrogen, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; or R₁₂ and R₁₃ may be joined together with anyintervening atoms to form an optionally substituted heterocycloalkylring;

or R₉ and R₁₁ may be joined together with any intervening atoms to forman optionally substituted heterocycloalkyl ring.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound or pharmaceutically acceptable salt of any one of compoundsdescribed herein. The pharmaceutical composition may be formulated in aform which is a tablet, capsule, powder, liquid, suspension,suppository, or aerosol. The pharmaceutical composition may be packagedwith instructions for using the composition to treat a subject sufferingfrom cancer.

In another aspect, the present disclosure provides a method of treatingcancer in a subject which comprises administering to a subject in needthereof a therapeutically effective amount of a compound orpharmaceutically acceptable salt of any one of the compounds describedherein. The cancer may be colon carcinoma, pancreatic cancer, breastcancer, ovarian cancer, prostate cancer, thyroid cancer, fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, non-small cell lungcancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,melanoma, neuroblastoma, retinoblastoma, leukemia, acute lymphocyticleukemia and acute myelocytic leukemia (myeloblastic, promyelocytic,myelomonocytic, monocytic and erythroleukemia); chronic leukemia(chronic myelocytic (granulocytic) leukemia and chronic lymphocyticleukemia); and polycythemia vera, lymphoma (Hodgkin's disease andnon-Hodgkin's disease), multiple myeloma, Waldenstrom'smacroglobulinemia, or heavy chain disease. In a further embodiment, thecancer is melanoma, non-small cell lung cancer, thyroid cancer, ovariancancer, or colon cancer. The melanoma may be unresectable or metastaticmelanoma.

In another aspect, the present disclosure provides a method of treatinga disorder mediated by Raf in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound or pharmaceutically acceptable salt of any one of the compoundsdescribed herein.

In another aspect, the present disclosure provides a method of treatinga disorder in a subject in need thereof, comprising: a) determining thepresence or absence of a B-Raf (BRAF) mutation in a biological sampleisolated from the subject; and b) if a BRAF mutation is determined to bepresent in the subject, administering to the subject a therapeuticallyeffective amount of a compound or pharmaceutically acceptable salt ofany one of the compounds described herein.

The BRAF mutation may be V600E or may be in codon 600. In someembodiments, determining the presence of absence of the BRAF mutationcomprises amplifying B-raf nucleic acid from the biological sample andsequencing the amplified nucleic acid. In some other embodiments,determining the presence of absence of the BRAF mutation comprisesdetecting a mutant B-raf polypeptide in the biological sample using abinding agent to a mutant B-raf polypeptide. The binding agent may be anantibody. The biological sample may be isolated from a tumor of thesubject.

In some embodiments, the disorder is cancer. The cancer may be coloncarcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostatecancer, thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonalcarcinoma, Wilms' tumor, cervical cancer, testicular tumor, lungcarcinoma, small cell lung carcinoma, non-small cell lung cancer,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,melanoma, neuroblastoma, retinoblastoma, leukemia, acute lymphocyticleukemia and acute myelocytic leukemia (myeloblastic, promyelocytic,myelomonocytic, monocytic and erythroleukemia); chronic leukemia(chronic myelocytic (granulocytic) leukemia and chronic lymphocyticleukemia); and polycythemia vera, lymphoma (Hodgkin's disease andnon-Hodgkin's disease), multiple myeloma, Waldenstrom'smacroglobulinemia, or heavy chain disease. In a further embodiment, thecancer is melanoma, non-small cell lung cancer, thyroid cancer, ovariancancer, or colon cancer. The melanoma may be unresectable or metastaticmelanoma.

The treatment method described herein may further comprise administeringan additional anti-cancer and/or cytotoxic agent.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference in their entiretiesto the same extent as if each individual publication, patent, or patentapplication was specifically and individually indicated to beincorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following words and phrases are generally intendedto have the meanings as set forth below, except to the extent that thecontext in which they are used indicates otherwise.

The following abbreviations and terms have the indicated meaningsthroughout:

-   AcOH=acetic acid-   Boc=tert-butoxycarbonyl-   c-=cyclo-   DCC=dicyclohexylcarbodiimide-   DCM=dichloromethane-   DIEA=N,N-diisopropylethylamine-   DMAP=4-dimethylaminopyridine-   EDC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-   eq=equivalent(s)-   Et=ethyl-   EtOAc or EA=ethyl acetate-   EtOH=ethanol-   g=gram-   h or hr=hour-   HBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBt=hydroxybenzotriazole-   HPLC=high pressure liquid chromatography-   i-=iso-   kg or Kg=kilogram-   L or 1=liter-   LC/MS=LCMS=liquid chromatography-mass spectrometry-   LRMS=low resolution mass spectrometry-   m/z=mass-to-charge ratio-   Me=methyl-   MeOH=methanol-   mg=milligram-   min=minute-   mL=milliliter-   mmol=millimole-   n-=normal-   NaOAc=sodium acetate-   PE=petroleum ether-   Ph=phenyl-   Prep=preparative-   quant.=quantitative-   RP-HPLC=reverse phase-high pressure liquid chromatography-   rt or RT=room temperature-   s-=sec-=secondary-   t-=tert-=tertiary-   THF=tetrahydrofuran-   TLC=thin layer chromatography-   UV=ultraviolet

As used herein, when any variable occurs more than one time in achemical formula, its definition on each occurrence is independent ofits definition at every other occurrence.

As used herein, a dash (“-”) that is not between two letters or symbolsis used to indicate a point of attachment for a substituent. Forexample, —CONH₂ is attached through the carbon atom.

As used herein, “optional” or “optionally” is meant that thesubsequently described event or circumstance may or may not occur, andthat the description includes instances wherein the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted alkyl” encompasses both “alkyl” and “substitutedalkyl” as defined below. It will be understood by those skilled in theart, with respect to any group containing one or more substituents, thatsuch groups are not intended to introduce any substitution orsubstitution patterns that are sterically impractical, syntheticallynon-feasible and/or inherently unstable.

As used herein, “alkyl” refers to straight chain and branched chainhaving the indicated number of carbon atoms, usually from 1 to 20 carbonatoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. Forexample C₁-C₆ alkyl encompasses both straight and branched chain alkylof from 1 to 6 carbon atoms. When an alkyl residue having a specificnumber of carbons is named, all branched and straight chain versionshaving that number of carbons are intended to be encompassed; thus, forexample, “butyl” is meant to include n-butyl, sec-butyl, isobutyl andt-butyl; “propyl” includes n-propyl and isopropyl. “Lower alkyl” refersto alkyl groups having one to six carbons. Examples of alkyl groupsinclude methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,3-hexyl, 3-methylpentyl, and the like. Alkylene is a subset of alkyl,referring to the same residues as alkyl, but having two points ofattachment. Alkylene groups will usually have from 2 to 20 carbon atoms,for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. Forexample, C₀ alkylene indicates a covalent bond and C₁ alkylene is amethylene group.

As used herein, “alkenyl” refers to an unsaturated branched orstraight-chain alkyl group having at least one carbon-carbon double bondderived by the removal of one molecule of hydrogen from adjacent carbonatoms of the parent alkyl. The group may be in either the cis or transconfiguration about the double bond(s). Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl;and the like. In certain embodiments, an alkenyl group has from 2 to 20carbon atoms and in other embodiments, from 2 to 6 carbon atoms. “Loweralkenyl” refers to alkenyl groups having two to six carbons.

As used herein, “alkynyl” refers to an unsaturated branched orstraight-chain alkyl group having at least one carbon-carbon triple bondderived by the removal of two molecules of hydrogen from adjacent carbonatoms of the parent alkyl. Typical alkynyl groups include, but are notlimited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl;butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and thelike. In certain embodiments, an alkynyl group has from 2 to 20 carbonatoms and in other embodiments, from 3 to 6 carbon atoms. “Loweralkynyl” refers to alkynyl groups having two to six carbons.

As used herein, “cycloalkyl” refers to a non-aromatic carbocyclic ring,usually having from 3 to 7 ring carbon atoms. The ring may be saturatedor have one or more carbon-carbon double bonds. Examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, and cyclohexenyl, as well as bridged and caged ring groupssuch as norbomane.

As used herein, “alkoxy” refers to an alkyl group of the indicatednumber of carbon atoms attached through an oxygen bridge such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy,hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like.Alkoxy groups will usually have from 1 to 7 carbon atoms attachedthrough the oxygen bridge. “Lower alkoxy” refers to alkoxy groups havingone to six carbons.

As used herein, “acyl” refers to the groups H—C(O)—; (alkyl)-C(O)—;(cycloalkyl)-C(O)—; (aryl)-C(O)—; (heteroaryl)-C(O)—; and(heterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality and wherein alkyl,cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as describedherein. Acyl groups have the indicated number of carbon atoms, with thecarbon of the keto group being included in the numbered carbon atoms.For example a C₂ acyl group is an acetyl group having the formulaCH₃(C═O)—.

As used herein, “formyl” refers to the group —C(O)H.

As used herein, “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached through the carbonyl carbon wherein the alkoxygroup has the indicated number of carbon atoms. Thus a C₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atomsattached through its oxygen to a carbonyl linker.

As used herein, “azido” refers to the group —N₃.

As used herein, “amino” refers to the group —NH₂.

As used herein, “mono- and di-(alkyl)amino” refers to secondary andtertiary alkyl amino groups, wherein the alkyl groups are as definedabove and have the indicated number of carbon atoms. The point ofattachment of the alkylamino group is on the nitrogen. Examples of mono-and di-alkylamino groups include ethylamino, dimethylamino, andmethyl-propyl-amino.

As used herein, “aminocarbonyl” refers to the group —CONR^(b)R^(c),where

R^(b) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, or optionallysubstituted alkoxy; and

R^(c) is hydrogen or optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c) taken together with the nitrogen to which they arebound, form an optionally substituted 4- to 8-memberednitrogen-containing heterocycloalkyl which optionally includes 1 or 2additional heteroatoms chosen from O, N, and S in the heterocycloalkylring;

where each substituted group is independently substituted with one ormore substituents independently C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, orheteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl),—N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl),—C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄ haloalkyl,—OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄alkyl), —NHSO₂(phenyl), or —NHSO₂(C₁-C₄ haloalkyl).

As used herein, “aryl” refers to: 6-membered carbocyclic aromatic rings,for example, benzene; bicyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, naphthalene, indane, andtetralin; and tricyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, fluorene.

For example, aryl includes 6-membered carbocyclic aromatic rings fusedto a 4- to 8-membered heterocycloalkyl ring containing 1 or moreheteroatoms chosen from N, O, and S. For such fused, bicyclic ringsystems wherein only one of the rings is a carbocyclic aromatic ring,the point of attachment may be at the carbocyclic aromatic ring or theheterocycloalkyl ring. Bivalent radicals formed from substituted benzenederivatives and having the free valences at ring atoms are named assubstituted phenylene radicals. Bivalent radicals derived from univalentpolycyclic hydrocarbon radicals whose names end in “-yl” by removal ofone hydrogen atom from the carbon atom with the free valence are namedby adding “-idene” to the name of the corresponding univalent radical,e.g. a naphthyl group with two points of attachment is termednaphthylidene. Aryl, however, does not encompass or overlap in any waywith heteroaryl, separately defined below. Hence, if one or morecarbocyclic aromatic rings is fused with a heterocycloalkyl aromaticring, the resulting ring system is heteroaryl, not aryl, as definedherein.

As used herein, “aryloxy” refers to the group —O-aryl.

As used herein, “aralkyl” refers to the group -alkyl-aryl.

As used herein, “carbamimidoyl” refers to the group —C(═NH)—NH2.

As used herein, “substituted carbamimidoyl” refers to the group—C(═NR^(e))—NR^(f)R^(g) where

R^(e) is hydrogen, cyano, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, or optionally substituted heterocycloalkyl; and

R^(f) and R^(g) are independently hydrogen optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, or optionally substitutedheterocycloalkyl,

provided that at least one of R^(e), R^(f), and R^(g) is not hydrogenand wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl refer respectively to alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5,for example, up to 3) hydrogen atoms are replaced by a substituentindependently —R^(a), —OR^(b), optionally substituted amino (including—NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—NR^(b)C(NR^(c))NR^(b)R^(c), —NR^(b)C(NCN)NR^(b)R^(c), and—NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo (as a substituent forcycloalkyl, heterocycloalkyl, and heteroaryl), optionally substitutedacyl (such as —COR^(b)), optionally substituted alkoxycarbonyl (such as—CO₂R^(b)), aminocarbonyl (such as —CONR^(b)R^(c)), —OCOR^(b),—OCO₂R^(a), —OCONR^(b)R^(c), —OP(O)(OR^(b))OR, sulfanyl (such asSR^(b)), sulfinyl (such as —SOR^(a)), or sulfonyl (such as —SO₂R^(a) and—SO₂NR^(b)R^(c)),

where R^(a) is optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, or optionally substituted heteroaryl;

R^(b) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedaryl, or optionally substituted heteroaryl; and

R^(c) is hydrogen or optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently C₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₄alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo (asa substituent for cycloalkyl, heterocycloalkyl, or heteroaryl), —CO₂H,—C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl),—CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO2(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), or —NHSO₂(C₁-C₄haloalkyl).

As used herein, “halo” refers to fluoro, chloro, bromo, and iodo, andthe term “halogen” includes fluorine, chlorine, bromine, and iodine.

As used herein, “haloalkyl” refers to alkyl as defined above having thespecified number of carbon atoms, substituted with 1 or more halogenatoms, up to the maximum allowable number of halogen atoms. Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

As used herein, “heteroaryl” refers to:

5- to 7-membered aromatic, monocyclic rings containing one or more, forexample, from 1 to 4, or in certain embodiments, from 1 to 3,heteroatoms chosen from N, O, and S, with the remaining ring atoms beingcarbon;

bicyclic heterocycloalkyl rings containing one or more, for example,from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosenfrom N, O, and S, with the remaining ring atoms being carbon and whereinat least one heteroatom is present in an aromatic ring; and

tricyclic heterocycloalkyl rings containing one or more, for example,from 1 to 5, or in certain embodiments, from 1 to 4, heteroatoms chosenfrom N, O, and S, with the remaining ring atoms being carbon and whereinat least one heteroatom is present in an aromatic ring.

For example, heteroaryl includes a 5- to 7-membered heterocycloalkyl,aromatic ring fused to a 4- to 8-membered cycloalkyl or heterocycloalkylring. For such fused, bicyclic heteroaryl ring systems wherein only oneof the rings contains one or more heteroatoms, the point of attachmentmay be at either ring. When the total number of S and O atoms in theheteroaryl group exceeds 1, those heteroatoms are not adjacent to oneanother. In certain embodiments, the total number of S and O atoms inthe heteroaryl group is not more than 2. In certain embodiments, thetotal number of S and O atoms in the aromatic heterocycle is not morethan 1. Examples of heteroaryl groups include, but are not limited to,(as numbered from the linkage position assigned priority 1), 2-pyridyl,3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl,3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolyl, isoxazolyl, oxazolyl,thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiophenyl, furanyl,pyrrolyl, benzofuranyl, benzoimidazolyl, indolyl, pyridazinyl,triazolyl, quinolinyl, quinoxalinyl, pyrazolyl, and5,6,7,8-tetrahydroisoquinolinyl. Bivalent radicals derived fromunivalent heteroaryl radicals whose names end in “-yl” by removal of onehydrogen atom from the atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical, e.g. apyridyl group with two points of attachment is a pyridylidene.Heteroaryl does not encompass or overlap with aryl, cycloalkyl, orheterocycloalkyl, as defined herein.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O⁻) substituents, such as pyridinyl N-oxides.

As used herein, “heterocycloalkyl” refers to a single, non-aromaticring, usually with 3 to 8 ring atoms, containing at least 2 carbon atomsin addition to 1-3 heteroatoms independently chosen from oxygen, sulfur,and nitrogen, as well as combinations comprising at least one of theforegoing heteroatoms. The ring may be saturated or have one or morecarbon-carbon double bonds. Suitable heterocycloalkyl groups include butare not limited to, for example, pyrrolidinyl, morpholinyl, piperidinyl,piperazinyl, azetidinyl, diazepanyl, diazocanyl, pyrrolidinyl,morpholinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl,dihydrofuranyl, and tetrahydrofuranyl. Substituted heterocycloalkyl canalso include ring systems substituted with one or more oxo (═O) or oxide(—O⁻) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

“Heterocycloalkyl” also includes bicyclic ring systems wherein onenon-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2carbon atoms in addition to 1-3 heteroatoms independently chosen fromoxygen, sulfur, and nitrogen, as well as combinations comprising atleast one of the foregoing heteroatoms; and the other ring, usually with3 to 7 ring atoms, optionally contains 1-3 heteratoms independentlychosen from oxygen, sulfur, and nitrogen and is not aromatic.

As used herein, “sulfanyl” refers to the groups: —S-(optionallysubstituted (C₁-C₆)alkyl), —S-(optionally substituted cycloalkyl),—S-(optionally substituted aryl), —S— (optionally substitutedheteroaryl), and —S-(optionally substituted heterocycloalkyl). Hence,sulfanyl includes the group C₁-C₆ alkylsulfanyl.

As used herein, “sulfinyl” refers to the groups: —S(O)-(optionallysubstituted (C₁-C₆)alkyl), —S(O)-(optionally substituted cycloalkyl),—S(O)-(optionally substituted aryl), —S(O)-optionally substitutedheteroaryl), —S(O)-(optionally substituted heterocycloalkyl); and—S(O)-(optionally substituted amino).

As used herein, “sulfonyl” refers to the groups: —S(O₂)-(optionallysubstituted (C₁-C₆)alkyl), —S(O₂)-(optionally substituted cycloalkyl),—S(O₂)-(optionally substituted aryl), —S(O₂)-(optionally substitutedheteroaryl), —S(O₂)-(optionally substituted heterocycloalkyl), and—S(O₂)-(optionally substituted amino).

As used herein, “substituted” refers to any one or more hydrogens on thedesignated atom or group is replaced with a selection from the indicatedgroup, provided that the designated atom's normal valence is notexceeded. When a substituent is oxo (i.e. ═O) then 2 hydrogens on theatom are replaced. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds oruseful synthetic intermediates. A stable compound or stable structure ismeant to imply a compound that is sufficiently robust to surviveisolation from a reaction mixture, and subsequent formulation as anagent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

As used herein, the terms “substituted” alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl, unless otherwise expressly defined,refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl wherein one or more (such as up to 5, for example, up to 3)hydrogen atoms are replaced by a substituent independently

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, azido,nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),optionally substituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), or sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)), where

R^(a) is optionally substituted C₁-C₆ alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, or optionally substituted heteroaryl; R^(b) ishydrogen, optionally substituted C₁-C₆ alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; and

R^(c) is hydrogen or optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently C₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₄alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo (asa substituent for cycloalkyl or heterocycloalkyl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), or —NHSO₂(C₁-C₄haloalkyl).

As used herein, “substituted acyl” refers to the groups (substitutedalkyl)-C(O)—; (substituted cycloalkyl)-C(O)—; (substituted aryl)-C(O)—;(substituted heteroaryl)-C(O)—; and (substitutedheterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality and wherein substitutedalkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, referrespectively to alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl wherein one or more (such as up to 5, for example, upto 3) hydrogen atoms are replaced by a substituent independently —R^(a),—OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl or heterocycloalkyl), optionallysubstituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), or sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)),

where R^(a) is optionally substituted C₁-C₆ alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, or optionally substituted heteroaryl;

R^(b) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; and

R^(c) is hydrogen or optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently C₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₄alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo (asa substituent for cycloalkyl or heterocycloalkyl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), or —NHSO₂(C₁-C₄haloalkyl).

As used herein, “substituted alkoxy” refers to alkoxy wherein the alkylconstituent is substituted (i.e. —O-(substituted alkyl)) wherein“substituted alkyl” refers to alkyl wherein one or more (such as up to5, for example, up to 3) hydrogen atoms are replaced by a substituentindependently

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl or heterocycloalkyl), optionallysubstituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)),where R^(a) is optionally substituted C₁-C₆ alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, or optionally substituted heteroaryl;

R^(b) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; and

R^(c) is hydrogen or optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently C₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₄alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo (asa substituent for cycloalkyl or heterocycloalkyl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), or —NHSO₂(C₁-C₄haloalkyl).

In some embodiments, a substituted alkoxy group is “polyalkoxy” or —O—(optionally substituted alkylene)-(optionally substituted alkoxy), andincludes groups such as —OCH₂CH₂OCH₃, and residues of glycol ethers suchas polyethyleneglycol, and —O(CH₂CH₂O)_(x)CH₃, where x is an integer of2-20, such as 2-10, and for example, 2-5. Another substituted alkoxygroup is hydroxyalkoxy or —OCH₂(CH₂)_(y)OH, where y is an integer of1-10, such as 1-4.

As used herein, “substituted alkoxycarbonyl” refers to the group(substituted alkyl)-O—C(O)— wherein the group is attached to the parentstructure through the carbonyl functionality and wherein substitutedrefers to alkyl wherein one or more (such as up to 5, for example, up to3) hydrogen atoms are replaced by a substituent independently

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl or heterocycloalkyl), optionallysubstituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)),where R^(a) is optionally substituted C₁-C₆ alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, or optionally substituted heteroaryl;

R^(b) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; and

R^(c) is hydrogen or optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently C₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₄alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo (asa substituent for cycloalkyl or heterocycloalkyl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), or —NHSO₂(C₁-C₄haloalkyl).

As used herein, “substituted amino” refers to the group —NHR^(d) or—NR^(d)R^(e) wherein R^(d) is hydroxyl, formyl, optionally substitutedalkoxy, optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted acyl, optionally substituted carbamimidoyl,aminocarbonyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocycloalkyl, optionallysubstituted alkoxycarbonyl, sulfinyl and sulfonyl, and wherein R^(e) ischosen from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, or optionally substituted heterocycloalkyl, and whereinsubstituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroarylrefer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl wherein one or more (such as up to 5, for example, up to 3)hydrogen atoms are replaced by a substituent independently —R^(a),—OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl or heterocycloalkyl), optionallysubstituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), or sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)), whereinR^(a) is optionally substituted C₁-C₆ alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted aryl, oroptionally substituted heteroaryl;

R^(b) is H, optionally substituted C₁-C₆ alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; and

R^(c) is hydrogen or optionally substituted C₁-C₄ alkyl; or R^(b) andR^(c), and the nitrogen to which they are attached, form an optionallysubstituted heterocycloalkyl group; and wherein each optionallysubstituted group is unsubstituted or independently substituted with oneor more, such as one, two, or three, substituents independently chosenfrom C₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₄alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo (as asubstituent for cycloalkyl or heterocycloalkyl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), or —NHSO₂(C₁-C₄haloalkyl); and

wherein optionally substituted acyl, optionally substitutedalkoxycarbonyl, sulfinyl and sulfonyl are as defined herein.

The term “substituted amino” also refers to N-oxides of the groups—NHR^(d), and NR^(d)R^(d) each as described above. N-oxides can beprepared by treatment of the corresponding amino group with, forexample, hydrogen peroxide or m-chloroperoxybenzoic acid. The personskilled in the art is familiar with reaction conditions for carrying outthe N-oxidation.

Compounds described herein include, but are not limited to, theiroptical isomers, racemates, and other mixtures thereof. In thosesituations, the single enantiomers or diastereomers, i.e., opticallyactive forms, can be obtained by asymmetric synthesis or by resolutionof the racemates. Resolution of the racemates can be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column. In addition,compounds include Z- and E-forms (or cis- and trans-forms) of compoundswith carbon-carbon double bonds. Where compounds described herein existin various tautomeric forms, the term “compound” is intended to includeall tautomeric forms of the compound.

Compounds of Formula I also include crystalline and amorphous forms ofthose compounds, including, for example, polymorphs, pseudopolymorphs,solvates (including hydrates), unsolvated polymorphs (includinganhydrates), conformational polymorphs, and amorphous forms of thecompounds, as well as mixtures thereof. “Crystalline form,” “polymorph,”and “novel form” may be used interchangeably herein, and are meant toinclude all crystalline and amorphous forms of the compound, including,for example, polymorphs, pseudopolymorphs, solvates (includinghydrates), unsolvated polymorphs (including anhydrates), conformationalpolymorphs, and amorphous forms, as well as mixtures thereof, unless aparticular crystalline or amorphous form is referred to. Similarly,“pharmaceutically acceptable forms” of compounds of Formula I alsoinclude crystalline and amorphous forms of those compounds, including,for example, polymorphs, pseudopolymorphs, solvates (includinghydrates), unsolvated polymorphs (including anhydrates), conformationalpolymorphs, and amorphous forms of the pharmaceutically acceptablesalts, as well as mixtures thereof.

A “solvate” is formed by the interaction of a solvent and a compound.The term “compound” is intended to include solvates of compounds.Similarly, “pharmaceutically acceptable salts” includes solvates ofpharmaceutically acceptable salts. Suitable solvates arepharmaceutically acceptable solvates, such as hydrates, includingmonohydrates and hemi-hydrates.

Compounds of Formula I also include other pharmaceutically acceptableforms of the recited compounds, including chelates, non-covalentcomplexes, prodrugs, and mixtures thereof.

A “chelate” is formed by the coordination of a compound to a metal ionat two (or more) points. The term “compound” is intended to includechelates of compounds. Similarly, “pharmaceutically acceptable salts”includes chelates of pharmaceutically acceptable salts.

A “non-covalent complex” is formed by the interaction of a compound andanother molecule wherein a covalent bond is not formed between thecompound and the molecule. For example, complexation can occur throughvan der Waals interactions, hydrogen bonding, and electrostaticinteractions (also called ionic bonding). Such non-covalent complexesare included in the term “compound”. Similarly, pharmaceuticallyacceptable salts include “non-covalent complexes” of pharmaceuticallyacceptable salts.

The term “hydrogen bond” refers to a form of association between anelectronegative atom (also known as a hydrogen bond acceptor) and ahydrogen atom attached to a second, relatively electronegative atom(also known as a hydrogen bond donor). Suitable hydrogen bond donor andacceptors are well understood in medicinal chemistry.

“Hydrogen bond acceptor” refers to a group comprising an oxygen ornitrogen, such as an oxygen or nitrogen that is sp²-hybridized, an etheroxygen, or the oxygen of a sulfoxide or N-oxide.

The term “hydrogen bond donor” refers to an oxygen, nitrogen, orheteroaromatic carbon that bears a hydrogen.group containing a ringnitrogen or a heteroaryl group containing a ring nitrogen.

The compounds disclosed herein can be used in different enrichedisotopic forms, e.g., enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or¹⁴C. In one particular embodiment, the compound is deuterated at leastone position. Such deuterated forms can be made by the proceduredescribed in U.S. Pat. Nos. 5,846,514 and 6,334,997. As described inU.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve theefficacy and increase the duration of action of drugs.

Deuterium substituted compounds can be synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp;George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compoundsvia Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21;and Evans, E. Anthony. Synthesis of radiolabeled compounds, J.Radioanal. Chem., 1981, 64(1-2), 9-32.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOOC—(CH₂)_(n)—COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if the compounds described herein are obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

“Prodrugs” described herein include any compound that becomes a compoundof Formula I when administered to a subject, e.g., upon metabolicprocessing of the prodrug. Similarly, “pharmaceutically acceptablesalts” includes “prodrugs” of pharmaceutically acceptable salts.Examples of prodrugs include derivatives of functional groups, such as acarboxylic acid group, in the compounds of Formula I. Exemplary prodrugsof a carboxylic acid group include, but are not limited to, carboxylicacid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters,and aryloxyalkyl esters. Other exemplary prodrugs include lower alkylesters such as ethyl ester, acyloxyalkyl esters such aspivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives.

Other exemplary prodrugs include amides of carboxylic acids. Exemplaryamide prodrugs include metabolically labile amides that are formed, forexample, with an amine and a carboxylic acid. Exemplary amines includeNH₂, primary, and secondary amines such as NHR^(x), and NR^(x)R^(y),wherein R^(x) is hydrogen, (C₁-C₁₈)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, (C₆-C₁₄)-aryl which is unsubstitutedor substituted by a residue (C₁-C₂)-alkyl, (C₁-C₂)-alkoxy, fluoro, orchloro; heteroaryl-, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl- where aryl isunsubstituted or substituted by a residue (C₁-C₂)-alkyl, (C₁-C₂)-alkoxy,fluoro, or chloro; or heteroaryl-(C₁-C₄)-alkyl- and in which R^(y) hasthe meanings indicated for R^(x) with the exception of hydrogen orwherein R^(x) and R^(Y), together with the nitrogen to which they arebound, form an optionally substituted 4- to 7-membered heterocycloalkylring which optionally includes one or two additional heteroatoms chosenfrom nitrogen, oxygen, and sulfur. A discussion of prodrugs is providedin T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, and in Design of Prodrugs, ed. H.Bundgaard, Elsevier, 1985.

As used herein, the terms “group”, “radical” or “fragment” aresynonymous and are intended to indicate functional groups or fragmentsof molecules attachable to a bond or other fragments of molecules.

As used herein, the term “leaving group” refers to the meaningconventionally associated with it in synthetic organic chemistry, i.e.,an atom or group displaceable under nucleophilic displacementconditions. Examples of leaving groups include, but are not limited to,dimethylhydroxylamino (e.g. Weinreb amide), halogen, alkane- orarylsulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

As used herein, the term “protective group” or “protecting group” refersto a group which selectively blocks one reactive site in amultifunctional compound such that a chemical reaction can be carriedout selectively at another unprotected reactive site in the meaningconventionally associated with it in synthetic chemistry. Certainprocesses of this invention rely upon the protective groups to blockcertain reactive sites present in the reactants. Examples of protectinggroups can be found in Wuts et al., Green's Protective Groups in OrganicSynthesis, (J. Wiley, 4th ed. 2006).

As used herein, the term “deprotection” or “deprotecting” refers to aprocess by which a protective group is removed after a selectivereaction is completed. Certain protective groups may be preferred overothers due to their convenience or relative ease of removal. Withoutbeing limiting, deprotecting reagents for protected amino or anilinogroup include strong acid such as trifluoroacetic acid (TFA),concentrated HCl, H₂SO₄, or HBr, and the like.

As used herein, “modulation” refers to a change in activity as a director indirect response to the presence of a chemical entity as describedherein, relative to the activity of in the absence of the chemicalentity. The change may be an increase in activity or a decrease inactivity, and may be due to the direct interaction of the compound withthe a target or due to the interaction of the compound with one or moreother factors that in turn affect the target's activity. For example,the presence of the chemical entity may, for example, increase ordecrease the target activity by directly binding to the target, bycausing (directly or indirectly) another factor to increase or decreasethe target activity, or by (directly or indirectly) increasing ordecreasing the amount of target present in the cell or organism.

As used herein, “active agent” is used to indicate a chemical entitywhich has biological activity. In certain embodiments, an “active agent”is a compound having pharmaceutical utility. For example an active agentmay be an anti-cancer therapeutic.

As used herein, “significant” refers to any detectable change that isstatistically significant in a standard parametric test of statisticalsignificance such as Student's T-test, where p<0.05.

As used herein, a “pharmaceutically acceptable” component is one that issuitable for use with humans and/or animals without undue adverse sideeffects (such as toxicity, irritation, and allergic response)commensurate with a reasonable benefit/risk ratio.

As used herein, “therapeutically effective amount” of a chemical entitydescribed herein refers to an amount effective, when administered to ahuman or non-human subject, to provide a therapeutic benefit such asamelioration of symptoms, slowing of disease progression, or preventionof disease.

“Treating” or “treatment” encompasses administration of at least onecompound of Formula I, or a pharmaceutically acceptable salt thereof, toa mammalian subject, particularly a human subject, in need of such anadministration and includes (i) arresting the development of clinicalsymptoms of the disease, such as cancer, (ii) bringing about aregression in the clinical symptoms of the disease, such as cancer,and/or (iii) prophylactic treatment for preventing the onset of thedisease, such as cancer.

As used herein, “cancer” refers to all types of cancer or neoplasm ormalignant tumors found in mammals, including carcinomas and sarcomas.Examples of cancer are cancer of the brain, breast, cervix, colon, head& neck, kidney, lung, non-small cell lung, melanoma, mesothelioma,ovary, sarcoma, stomach, uterus and Medulloblastoma.

As used herein, “subject” refers to a mammal that has been or will bethe object of treatment, observation or experiment. The methodsdescribed herein can be useful in both human therapy and veterinaryapplications. In some embodiments, the subject is a human.

The term “mammal” is intended to have its standard meaning, andencompasses humans, dogs, cats, sheep, and cows, for example.

As used herein, the terms “BRAF”, “B-raf”, “B-Raf” and the like are usedinterchangeably to refer to the gene or protein product of the gene.

A. Compounds

In one aspect, provided is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₁₀ are independently hydrogen,cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl,sulfonyl, optionally substituted alkoxy, optionally substitutedcycloalkyloxy, optionally substituted aryloxy, optionally substitutedheteroaryloxy, optionally substituted heterocycloalkyloxy, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted aryloxy, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocycloalkyl, optionallysubstituted amino, optionally substituted acyl, optionally substitutedalkoxycarbonyl, optionally substituted aminocarbonyl, optionallysubstituted aminosulfonyl, optionally substituted carbamimidoyl, oroptionally substituted alkynyl;

R₉ is hydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; and

R₁₁ is hydroxyl, formyl, optionally substituted alkoxy, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(NR₁₄)NR₁₂R₁₃,—C(NCN)NR₁₂R₁₃, or —SO₂NR₁₂R₁₃, where R₁₂ is optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; and R₁₃ and R₁₄ are independently hydrogen, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; or R₁₂ and R₁₃ may be joined together with anyintervening atoms to form an optionally substituted heterocycloalkylring;

or R₉ and R₁₁ may be joined together with any intervening atoms to forman optionally substituted heterocycloalkyl ring.

In some embodiments, R₁ is hydrogen, cyano, halo, hydroxy, carboxy,optionally substituted alkoxy, optionally substituted aryloxy,optionally substituted alkoxycarbonyl, optionally substituted alkyl,optionally substituted aryloxy, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocycloalkyl,optionally substituted amino, optionally substituted acyl, optionallysubstituted alkoxycarbonyl, optionally substituted aminocarbonyl,optionally substituted aminosulfonyl, optionally substitutedcarbamimidoyl, or optionally substituted alkynyl. In a furtherembodiment, R₁ is hydrogen, cyano, optionally substituted alkoxy,optionally substituted aryloxy, optionally substituted amino, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheterocycloalkyl, or optionally substituted heteroaryl. In anotherfurther embodiment, R₁ is optionally substituted aryl, optionallysubstituted heterocycloalkyl, or optionally substituted heteroaryl. Inanother embodiment, R₁ is optionally substituted morpholinyl, optionallysubstituted piperazinyl, optionally substituted pyrrolidinyl, optionallysubstituted piperidinyl, optionally substituted imidazolyl, optionallysubstituted pyrazolyl, or optionally substituted pyridyl. In otherembodiments, R₁ is chosen from pyrrolidinyl, morpholinyl, piperidinyl,piperazinyl, diazepanyl, and diazocanyl, each of which is optionallysubstituted with one or two groups independently chosen from hydroxyl,amino, oxo, and lower alkyl optionally substituted with hydroxy oramino. In other embodiments, R₁ is chosen from pyrrolidin-1-yl,morpholin-4-yl (numbered wherein the oxygen is assigned priority 1),piperidin-1-yl, piperazin-1-yl, 1,4-diazepan-1-yl, and1-4,-diazocan-1-yl, each of which is optionally substituted with one ortwo groups independently chosen from hydroxyl, amino, oxo, and loweralkyl optionally substituted with hydroxy or amino. In otherembodiments, R₁ is chosen from hydrogen, cyano, lower alkyl, loweralkoxy, amino, 1H-imidazol-1-yl optionally substituted with lower alkyl,1H-pyrazol-4-yl optionally substituted with lower alkyl, 1H-pyrazol-3-yloptionally substituted with lower alkyl, pyridin-2-yl optionallysubstituted with lower alkyl, pyridin-3-yl optionally substituted withlower alkyl, and pyridin-4-yl optionally substituted with lower alkyl.In some embodiments, R₁ is chosen from hydrogen, cyano, lower alkyl,lower alkoxy, amino, imidazolyl optionally substituted with lower alkyl,pyrazolyl optionally substituted with lower alkyl, pyridinyl optionallysubstituted with lower alkyl. In some embodiments, R₁ is chosen fromhydrogen, methyl, cyano, methoxy, imidazolyl, methyl-imidazolyl,pyrazolyl, pyridinyl, methylpyridinyl, morpholinyl, pyrrolidinyl, andpiperazinyl. In some embodiments, R₁ is chosen from hydrogen, methyl,cyano, methoxy, 1H-imidazol-1-yl, 2-methyl-1H-imidazol-1-yl,5-methyl-1H-imidazol-1-yl, 4-methyl-1H-imidazol-1-yl, 1H-pyrazol-4-yl,1H-pyrazol-3-yl, pyridin-3-yl, 6-methylpyridin-3-yl, pyridin-4-yl,morpholin-4-yl, pyrrolidin-1-yl, and piperazin-1-yl. In otherembodiments, R₁ is optionally substituted heteroaryl. For example, R₁ ispyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiophenyl,furanyl, pyrrolyl, benzofuranyl, benzoimidazolyl, indolyl, pyridazinyl,triazolyl, quinolinyl, quinoxalinyl, pyrazolyl, or5,6,7,8-tetrahydroisoquinolinyl. For example, R₁ is 2-pyridyl,3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl,3,5-pyrimidinyl, 2,3-pyrazolyl, 2,4-imidazolyl, isoxazolyl, oxazolyl,thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiophenyl, furanyl,pyrrolyl, benzofuranyl, benzoimidazolyl, indolyl, pyridazinyl,triazolyl, quinolinyl, quinoxalinyl, pyrazolyl, or5,6,7,8-tetrahydroisoquinolinyl. In yet other embodiments, R₁ isoptionally substituted heterocycloalkyl. For example, R₁ is pyrrolidinylsuch as 2-pyrrolidinyl, imidazolidinyl such as 2,4-imidazolidinyl,pyrazolidinyl such as 2,3-pyrazolidinyl, piperidyl such as 2-piperidyl,3-piperidyl, or 4-piperidyl, piperazinyl such as 2,5-piperazinyl,pyrrolidinyl, azetidinyl, pyranyl, dihydrofuranyl such as2,3-dihydrofuranyl, or 2,5-dihydrofuranyl, morpholinyl such as2-morpholinyl or 3-morpholinyl, piperidinyl N-oxide,morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl or1,1-dioxo-1-thiomorpholinyl.

In some embodiments, each of R₂, R₃, R₄, and R₅ is independentlyhydrogen, halo, cyano, optionally substituted alkoxy, or optionallysubstituted alkyl.

In some embodiments, R₂ is chosen from hydrogen, halo, alkoxy, andalkyl. In some embodiments, R₂ is hydrogen.

In some embodiments, R₃ is hydrogen, halo, alkoxy, or alkyl. In someembodiments, R₃ is hydrogen.

In some embodiments, R₄ is hydrogen, halo, alkoxy, or alkyl. In someembodiments, R₄ is hydrogen.

In some embodiments, R₅ is hydrogen, halo, alkoxy, or alkyl. In someembodiments, R₅ is hydrogen.

In some embodiments, R₂, R₃, R₄, and R₅ are hydrogen.

In some embodiments, each of R₆, R₇, R₈, and R₁₀ is hydrogen, cyano,halo, optionally substituted alkoxy, optionally substituted alkyl,optionally substituted acyl, optionally substituted alkoxycarbonyl,optionally substituted aminocarbonyl, or optionally substitutedaminosulfonyl. In some embodiments, each of R₆, R₇, R₈, and R₁₀ isindependently hydrogen, cyano, or halo.

In some embodiments, R₆ is hydrogen, cyano, or halo. In someembodiments, R₆ is hydrogen or halo. In some embodiments, R₆ ishydrogen. In some embodiments, R₆ is halo. In some embodiments, R₆ isfluoro.

In some embodiments, R₈ is hydrogen, cyano, or halo. In someembodiments, R₈ is hydrogen.

In some embodiments, R₁₀ is hydrogen, cyano, or halo. In someembodiments, R₁₀ is hydrogen or halo. In some embodiments, R₁₀ ishydrogen. In some embodiments, R₁₀ is halo. In some embodiments, R₁₀ isfluoro.

In some embodiments, R₇ is hydrogen, cyano, or halo. In someembodiments, R₇ is hydrogen or halo. In some embodiments, R₇ ishydrogen. In some embodiments, R₇ is halo. In some embodiments, R₇ isfluoro.

In some embodiments, R₆, R₇, R₈, and R₁₀ are hydrogen.

In some embodiments, R₆, R₇, and R₈ are hydrogen, and R₁₀ is fluoro.

In some embodiments, R₆, R₈, and R₁₀ are hydrogen, and R₇ is fluoro.

In some embodiments, R₉ is hydrogen or optionally substituted loweralkyl. In some embodiments, R₉ is hydrogen.

In some embodiments, R₁₁ is optionally substituted alkyl, —COR₁₂,—CO₂R₁₂, —CONR₁₂R₁₃, —C(NCN)NR₁₂R₁₃, or —SO₂NR₁₂R₁₃. In someembodiments, R₁₁ is —COR₁₂ or —CONR₁₂R₁₃.

In some embodiments, R₁₂ is optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl. Insome embodiments, R₁₂ is lower alkyl, aryl optionally substituted withone or two groups independently chosen from halo, cyano, lower alkyl,amino, and lower alkoxy, or heteroaryl optionally substituted with oneor two groups independently chosen from halo, cyano, lower alkyl, amino,and lower alkoxy. In some embodiments, R₁₂ is propyl, phenyl, pyridyl,fluoropyridinyl, chloropyridinyl, trifluoroethyl-pyridin-yl,fluorophenyl, chlorophenyl, trifluoromethylphenyl, difluorophenyl,chloro-fluorophenyl, fluoro-trifluoromethylphenyl,chloro-trifluoromethyl-phenyl, or cyano-trifluoromethylphenyl. In someembodiments, R₁₂ is propyl, phenyl, pyridyl, 5-fluoropyridin-3-yl,5-chloropyridin-3-yl, 2-(trifluoroethyl)pyridin-4-yl, 3-fluorophenyl,3-chlorophenyl, 3-trifluoromethyl-phenyl, 4-fluorophenyl,4-chlorophenyl, 3,4-di-fluoro-phenyl, 3,5-di-fluoro-phenyl,3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro-phenyl,3-fluoro-4-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl,3-chloro-4-trifluoromethyl-phenyl, 4-cyano-3-trifluoromethyl-phenyl, or4-chloro-3-trifluoromethyl-phenyl. In some embodiments, R₁₂ isoptionally substituted aryl. In some embodiments, R₁₂ is phenyloptionally substituted with one or more groups selected from the groupconsisting of H, —CH₃, —CH₂F, —CHF₂, —CF₃, F, Cl, Br, I, and CN. In someembodiments, R₁₂ is pyridyl optionally substituted with one or moregroups selected from the group consisting of H, —CH₃, —CH₂F, —CHF₂,—CF₃, trifluoroethyl, F, Cl, Br, I, and CN. In some embodiments, R₁₂ isoptionally substituted heteroaryl. In some embodiments, R₁₂ isheteroaryl optionally substituted with one or more groups selected fromthe group consisting of H, —CH₃, —CH₂F, —CHF₂, —CF₃, F, Cl, Br, I, andCN.

In some embodiments, R₁₃ is hydrogen or optionally substituted loweralkyl. In some embodiments, R₁₃ is hydrogen.

In some embodiments, R₁₂ and R₁₃ are joined together with anyintervening atoms to form an optionally substituted 4- to 8-memberedheterocycloalkyl ring. In some embodiments, R₁₂ and R₁₃ are joinedtogether to form a 4- to 8-membered heterocycloalkyl ring chosen frompyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and1-4,-diazocanyl, each of which is optionally substituted with one or twogroups independently chosen from hydroxyl, amino, oxo, and lower alkyloptionally substituted with hydroxy or amino. In some embodiments, R₁₂and R₁₃ are joined together to form a 4- to 8-membered heterocycloalkylring chosen from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl,piperazin-1-yl, and 1-4,-diazocan-1-yl, each of which is optionallysubstituted with one or two groups independently chosen from hydroxyl,amino, oxo, and lower alkyl optionally substituted with hydroxy oramino.

In some embodiments, R₁₄ is chosen from hydrogen and optionallysubstituted lower alkyl. In some embodiments, R₁₄ is hydrogen.

In some embodiments, R₉ and R₁₁ are joined together with any interveningatoms to form an optionally substituted 4- to 8-memberedheterocycloalkyl ring. In some embodiments, R₉ and R₁₁ are joinedtogether to form a 4- to 8-membered heterocycloalkyl ring chosen frompyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, diazepanyl, anddiazocanyl, each of which is optionally substituted with one or twogroups independently chosen from hydroxyl, amino, oxo, and lower alkyloptionally substituted with hydroxy or amino. In some embodiments, R₉and R₁₁ are joined together to form a 4- to 8-membered heterocycloalkylring chosen from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl,piperazin-1-yl, 1,4-diazepan-1-yl, and 1-4,-diazocan-1-yl, each of whichis optionally substituted with one or two groups independently chosenfrom hydroxyl, amino, oxo, and lower alkyl optionally substituted withhydroxy or amino.

In another aspect, the present disclosure provides a compound orpharmaceutically acceptable salt chosen from the group consisting of:

-   1-(3-fluorophenyl)-3-(4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-chlorophenyl)-3-(4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(4-chloro-3-fluorophenyl)-3-(4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-methylquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-methoxyquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(2-hydroxyethoxy)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-(2-aminoethoxy)quinoxaline-6-carbonyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(2-methoxyethoxy)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-cyanoquinoxaline-6-carbonyl)phenyl)urea,-   1-(3-fluorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-fluorophenyl)-3-(4-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-fluorophenyl)-3-(4-(3-(6-methylpyridin-3-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-(1H-imidazol-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(4-methyl-1H-imidazol-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(5-methyl-1H-imidazol-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-(1H-pyrazol-4-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,-   1-(3-fluorophenyl)-3-(4-(3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-fluorophenyl)-3-(4-(3-(6-(piperazin-1-yl)pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-fluorophenyl)-3-(4-(3-(4-(piperazin-1-yl)phenyl)quinoxaline-6-carbonyl)phenyl)urea,-   N-(4-(7-(4-(3-(3-fluorophenyl)ureido)benzoyl)quinoxalin-2-yl)phenyl)methanesulfonamide,-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-cyanoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(3-(pyrrolidin-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-((2-hydroxyethyl)amino)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-((2-aminoethyl)amino)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(4-(3-((2-hydroxyethyl)amino)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(4-(3-((2-aminoethyl)amino)quinoxaline-6-carbonyl)-3-fluorophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea,-   1-(4-(3-(1H-pyrazol-3-yl)quinoxaline-6-carbonyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea,-   1-(4-(3-(1H-pyrazol-3-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,-   1-(3-chlorophenyl)-3-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-chlorophenyl)-3-(3,5-difluoro-4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-chlorophenyl)-3-(2-fluoro-4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-chlorophenyl)-3-(2,3,5-trifluoro-4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-methoxyquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-(2-hydroxyethoxy)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-(2-aminoethoxy)quinoxaline-6-carbonyl)-3-fluorophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-(2-methoxyethoxy)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)urea,-   1-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,-   1-(2-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,-   1-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-fluoro-4-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,-   1-(3-fluoro-4-(3-(6-methylpyridin-3-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-(1H-pyrazol-4-yl)quinoxaline-6-carbonyl)-3-fluorophenyl)-3-(3-fluorophenyl)urea,-   1-(3-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-(pyrrolidin-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-((2-hydroxyethyl)amino)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-((2-aminoethyl)amino)quinoxaline-6-carbonyl)-3-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(3-fluoro-4-(3-((2-hydroxyethyl)amino)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(2-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   3-fluoro-N-(4-(quinoxaline-6-carbonyl)phenyl)benzamide,-   3-chloro-N-(4-(quinoxaline-6-carbonyl)phenyl)benzamide,-   N-(4-(quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-3-fluoro-N-(4-(quinoxaline-6-carbonyl)phenyl)benzamide,-   4-chloro-N-(4-(quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   3-chloro-N-(4-(quinoxaline-6-carbonyl)phenyl)-4-(trifluoromethyl)benzamide,-   4-chloro-N-(4-(3-methylquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-N-(4-(3-methoxyquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-N-(4-(3-(2-hydroxyethoxy)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   N-(4-(3-(2-aminoethoxy)quinoxaline-6-carbonyl)phenyl)-4-chloro-3-(trifluoromethyl)benzamide,-   4-chloro-N-(4-(3-(2-methoxyethoxy)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-N-(4-(3-cyanoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   3-fluoro-N-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide,-   N-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-N-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-N-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   3-fluoro-N-(4-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)benzamide,-   3-fluoro-N-(4-(3-(6-methylpyridin-3-yl)quinoxaline-6-carbonyl)phenyl)benzamide,-   4-chloro-N-(4-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   N-(4-(3-(1H-imidazol-1-yl)quinoxaline-6-carbonyl)phenyl)-4-chloro-3-(trifluoromethyl)benzamide,-   4-chloro-N-(4-(3-(4-methyl-1H-imidazol-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-N-(4-(3-(5-methyl-1H-imidazol-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   N-(4-(3-(1H-pyrazol-4-yl)quinoxaline-6-carbonyl)phenyl)-3-fluorobenzamide,-   3-fluoro-N-(4-(3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-carbonyl)phenyl)benzamide,-   3-fluoro-N-(4-(3-(6-(piperazin-1-yl)pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)benzamide,-   3-fluoro-N-(4-(3-(4-(piperazin-1-yl)phenyl)quinoxaline-6-carbonyl)phenyl)benzamide,-   3-fluoro-N-(4-(3-(4-(methylsulfonamido)phenyl)quinoxaline-6-carbonyl)phenyl)benzamide,-   4-cyano-N-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-cyano-N-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   3-fluoro-N-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)benzamide,-   3-chloro-N-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)benzamide,-   3-chloro-N-(2-fluoro-4-(quinoxaline-6-carbonyl)phenyl)benzamide,-   3-chloro-N-(3,5-difluoro-4-(quinoxaline-6-carbonyl)phenyl)benzamide,-   3-chloro-N-(2,3,5-trifluoro-4-(quinoxaline-6-carbonyl)phenyl)benzamide,-   N-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-3-fluoro-N-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)benzamide,-   4-chloro-N-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-N-(2-fluoro-4-(quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   3-chloro-N-(3-fluoro-4-(quinoxaline-6-carbonyl)phenyl)-4-(trifluoromethyl)benzamide,-   4-chloro-N-(3-fluoro-4-(3-methoxyquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-N-(3-fluoro-4-(3-(2-hydroxyethoxy)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   N-(4-(3-(2-aminoethoxy)quinoxaline-6-carbonyl)-3-fluorophenyl)-4-chloro-3-(trifluoromethyl)benzamide,-   4-chloro-N-(3-fluoro-4-(3-(2-methoxyethoxy)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-N-(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)-3-(trifluoromethyl)benzamide,-   3-fluoro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide,-   3-fluoro-N-(2-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide,-   N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   3-fluoro-N-(3-fluoro-4-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)benzamide,-   3-fluoro-N-(3-fluoro-4-(3-(6-methylpyridin-3-yl)quinoxaline-6-carbonyl)phenyl)benzamide,-   4-chloro-N-(3-fluoro-4-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   N-(4-(3-(1H-imidazol-1-yl)quinoxaline-6-carbonyl)-3-fluorophenyl)-4-chloro-3-(trifluoromethyl)benzamide,-   N-(4-(3-(1H-pyrazol-4-yl)quinoxaline-6-carbonyl)-3-fluorophenyl)-3-fluorobenzamide,-   3-fluoro-N-(3-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-carbonyl)phenyl)benzamide,-   4-cyano-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   4-cyano-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,-   1-(3-chlorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-chlorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-fluorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea,-   1-(4-chlorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-fluorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-chlorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea,-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-fluorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea,-   1-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea,-   2-(4-cyano-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)acetamide,-   1-(4-(3-(piperidin-4-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea,-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperidin-4-yl)quinoxaline-6-carbonyl)phenyl)urea,-   1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(1-methyl-1H-pyrazol-3-yl)urea,-   1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)urea,-   1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(5-methylisoxazol-3-yl)urea,-   4-chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide,-   3-chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide,-   3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide,-   4-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide,-   3-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide,    and-   N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide,    and pharmaceutically acceptable salts thereof.

In yet another aspect, the present disclosure provides a compound chosenfrom the compounds set forth in Table 1 below and pharmaceuticallyacceptable salts thereof.

TABLE 1 Illustrative Compounds of the Present Invention Compound No.Chemical Name C011-(4-(quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)ureaC02 1-(3-fluorophenyl)-3-(4-(quinoxaline-6-carbonyl)phenyl)urea C031-(3-chlorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)ureaC041-(4-chlorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)ureaC051-(4-fluorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)ureaC061-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea, C071-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea C081-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea C091-(4-chlorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea C101-(4-fluorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea C111-(3-chlorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea C121-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea C131-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea C141-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea C151-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea C161-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea C171-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea C181-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea C191-(3-fluorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea C201-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea C211-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea C221-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea C231-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea C241-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea C251-(4-fhloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea C262-(4-cyano-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)acetamide C271-(4-(3-(piperidin-4-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea C281-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperidin-4-yl)quinoxaline-6-carbonyl)phenyl)urea C291-(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea C301-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)urea C311-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(1-methyl-1H-pyrazol-3-yl)urea C321-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)urea C331-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(5-methylisoxazol-3-yl)urea C343-fluoro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide C354-chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide C364-chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide C373-chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide C38N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide C393-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide C404-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide C413-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide C42N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide C434-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide

In some embodiments, a compound of Formula I binds to a kinaseincluding, but not limited to, Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf,B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR,EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1,Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha, Gsk3beta, HCK, Her2/Erbb2,Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2,Jnk3, KDR, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1,MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta,PKC theta, Plk1, Pyk2, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2,TrkA, TrkB, Yes, and Zap70, including any mutated versions thereof. Forexample, the compound of Formula I binds to a kinase selected from thegroup consisting of A-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Jnk1, Jnk2, Jnk3, Lck,Lyn, Met, Pim1, Pim2, Pim3, Pyk2, KDR, Src and Ret, and any mutatedversions thereof. In some embodiments, the compound of Formula I bindsto a kinase selected from the group consisting of A-Raf, B-Raf, B-RafV600E mutant, B-Raf V600E/T5291 mutant, or c-Raf-1. For example, thecompound of Formula I binds to a kinase which is B-Raf or B-Raf V600Emutant. In some embodiments, a compound of Formula I binds to a kinaseincluding, but not limited to, Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf,B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR,EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1,Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha, Gsk3beta, HCK, Her2/Erbb2,Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2,Jnk3, KDR, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1,MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta,PKC theta, Plk1, Pyk2, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2,TrkA, TrkB, Yes, and Zap70, including any mutated versions thereof, witha Kd which is lower than 50 μM, 25 μM, 10 μM, 5 μM, or 1 μM as measuredin an in vitro assay. For example, the compound of Formula I binds to akinase selected from the group consisting of A-Raf, B-Raf, B-Raf V600Emutant, B-Raf V600E/T5291 mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3,FGFR4, Jnk1, Jnk2, Jnk3, Lck, Lyn, Met, Pim1, Pim2, Pim3, Pyk2, KDR, Srcand Ret, and any mutated versions thereof with a Kd which is lower than50 μM, 25 μM, 10 μM, 5 μM, or 1 μM as measured in an in vitro assay. Insome embodiments, the compound of Formula I binds to a kinase selectedfrom the group consisting of A-Raf, B-Raf, B-Raf V600E mutant, B-RafV600E/T5291 mutant, or c-Raf-1 with a Kd which is lower than 50 μM, 25μM, 10 μM, 5 μM, or 1 μM as measured in an in vitro assay. For example,the compound of Formula I binds to a kinase which is B-Raf or B-RafV600E mutant with a Kd which is lower than 50 μM, 25 μM, 10 μM, 5 μM, or1 μM as measured in an in vitro assay.

In some embodiments, a compound of Formula I inhibits a kinaseincluding, but not limited to, Abl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf,B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR,EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1,Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha, Gsk3beta, HCK, Her2/Erbb2,Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2,Jnk3, KDR, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1,MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta,PKC theta, Plk1, Pyk2, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2,TrkA, TrkB, Yes, and Zap70, including any mutated versions thereof. Forexample, the compound of Formula I inhibits a kinase selected from thegroup consisting of A-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Jnk1, Jnk2, Jnk3, Lck,Lyn, Met, Pim1, Pim2, Pim3, Pyk2, KDR, Src and Ret, and any mutatedversions thereof. In some embodiments, the compound of Formula Iinhibits a kinase selected from the group consisting of A-Raf, B-Raf,B-Raf V600E mutant, B-Raf V600E/T5291 mutant, or c-Raf-1. For example,the compound of Formula I inhibits a kinase which is B-Raf or B-RafV600E mutant. In some embodiments, a compound of Formula I inhibits akinase including, but not limited to, Abl, Akt1, Akt2, Akt3, ALK, Alk5,A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk,EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4,Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha, Gsk3beta, HCK, Her2/Erbb2,Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2,Jnk3, KDR, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1,MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta,PKC theta, Plk1, Pyk2, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2,TrkA, TrkB, Yes, and Zap70, including any mutated versions thereof withan IC₅₀ in an in vitro assay of 10 μM, 5 μM, 2 μM, 1 μM, 500 nM, 200 nM,100 nM or less as ascertained in an in vitro kinase assay. For example,the compound of Formula I inhibits a kinase selected from the groupconsisting of A-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Jnk1, Jnk2, Jnk3, Lck,Lyn, Met, Pim1, Pim2, Pim3, Pyk2, KDR, Src and Ret, and any mutatedversions thereof with an IC₅₀ in an in vitro assay of 10 μM, 5 μM, 2 μM,1 μM, 500 nM, 200 nM, 100 nM or less as ascertained in an in vitrokinase assay. In some embodiments, the compound of Formula I inhibits akinase selected from the group consisting of A-Raf, B-Raf, B-Raf V600Emutant, B-Raf V600E/T5291 mutant, and c-Raf-1 with an IC₅₀ in an invitro assay of 10 μM, 5 μM, 2 μM, 1 μM, 500 nM, 200 nM, 100 nM or lessas ascertained in an in vitro kinase assay. For example, the compound ofFormula I inhibits a kinase which is B-Raf or B-Raf V600E mutant with anIC₅₀ in an in vitro assay of 10 μM, 5 μM, 2 μM, 1 μM, 500 nM, 200 nM,100 nM or less as ascertained in an in vitro kinase assay.

In some embodiments, the compound of Formula I inhibits the activity ofone or more kinases selected from the group consisting of A-Raf, B-Raf,B-Raf V600E mutant, B-Raf V600E/T5291 mutant, and c-Raf-1 with an IC₅₀in an in vitro assay of 1 μM, 500 nM, 200 nM, 100 nM, 50 nM, 25 nM orless as ascertained in an in vitro kinase assay.

In some embodiments, the compound of Formula I selectively inhibits theactivity of one or more kinases selected from the group consisting ofAbl, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4,CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2,Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn,Gsk3alpha, Gsk3beta, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta,Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, KDR, Kit, Lck, Lyn,MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB,PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plk1, Pyk2,ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, andZap70, including any mutated versions thereof. For example, the compoundof Formula I selectively inhibits the activity of one or more kinasesselected from the group consisting of A-Raf, B-Raf, B-Raf V600E mutant,B-Raf V600E/T5291 mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4,Jnk1, Jnk2, Jnk3, Lck, Lyn, Met, Pim1, Pim2, Pim3, Pyk2, KDR, Src andRet. In some embodiments, the compound of Formula I selectively inhibitsthe activity of one or more kinases selected from the group consistingof A-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291 mutant, andc-Raf-1.

In some embodiments, the compound of Formula I selectively inhibits theactivity of B-Raf, or B-Raf V600E mutant relative to one or more kinasesselected from the group consisting of ABL1, AKT1 (PKB alpha), AURKB(Aurora B), BLK, BTK, CDK1/cyclin B, CHEK1 (CHK1), CSF1R (FMS), CSNK1G2(CK1 gamma 2), EGFR (ErbB1), FGFR1, FGR, FLT3, FRAP1 (mTOR), FYN, IGF1R,IKBKB (IKK beta), INSR, KIT, LCK, LYN A, MAP2K1 (MEK1), MAP4K5 (KHS1),MAPK1 (ERK2), MAPK14 (p38 alpha), MAPKAPK2, MET (cMet), PDGFRB (PDGFRbeta), PIK3CA/PIK3R1 (p110 alpha/p85 alpha)PRKCB2 (PKC beta II), PTK2B(FAK2), PTK6 (Brk), RAF1 (cRAF) Y340D Y341D, RET, RPS6KB1 (p70S6K), SRC,SRMS (Srm), and YES1. In some embodiments, the compound of Formula Iselectively inhibits the activity of one or more kinases selected fromthe group consisting of A-Raf, B-Raf, B-Raf V600E mutant, B-RafV600E/T5291 mutant, and c-Raf-1 with an IC₅₀ which is ½, ⅓^(rd), ¼^(th),⅕^(th), 1/7^(th), 1/10^(th), 1/15^(th), 1/20^(th), 1/25^(th), 1/30^(th),1/40^(th), 1/50^(th), 1/100^(th), 1/150^(th), 1/200^(th), 1/300^(th),1/400^(th), 1/500^(th), 1/1000^(th), 1/2000^(th) or less than the IC₅₀for a kinase selected from the group consisting of ABL1, AKT1 (PKBalpha), AURKB (Aurora B), BLK, BTK, CDK1/cyclin B, CHEK1 (CHK1), CSF1R(FMS), CSNK1G2 (CK1 gamma 2), EGFR (ErbB1), FGFR1, FGR, FLT3, FRAP1(mTOR), FYN, IGF1R, IKBKB (IKK beta), INSR, KIT, LCK, LYN A, MAP2K1(MEK1), MAP4K5 (KHS1), MAPK1 (ERK2), MAPK14 (p38 alpha), MAPKAPK2, MET(cMet), PDGFRB (PDGFR beta), PIK3CA/PIK3R1 (p110 alpha/p85 alpha)PRKCB2(PKC beta II), PTK2B (FAK2), PTK6 (Brk), RAF1 (cRAF) Y340D Y341D, RET,RPS6KB1 (p70S6K), SRC, SRMS (Srm), and YES1.

In some embodiments, one or more compounds of Formula I are capable ofinhibiting cellular proliferation. For example, In some embodiments, oneor more compounds of Formula I inhibit proliferation of tumor cells ortumor cell lines. For example, such cell lines express a kinase which isB-raf or B-raf V600E mutant. In some embodiments, the compounds ofFormula I inhibit A375 or A549 cell proliferation in vitro or in an invivo model such as a xenograft mouse model. In some embodiments, invitro cultured A375 or A549 cell proliferation may be inhibited with anIC₅₀ of less than 100 μM, 75 μM, 50 μM, 25 μM, 15 μM, 10 μM, 5 μM, 3 μM,2 μM, 1 μM or less by one or more compounds of Formula I.

B. Methods of Making

Compounds disclosed herein may be prepared by the routes describedbelow. Materials used herein are either commercially available orprepared by synthetic methods generally known in the art. These schemesare not limited to the compounds listed or by any particularsubstituents, which are employed for illustrative purposes. Althoughvarious steps of are described and depicted in Schemes A-C, the steps insome cases may be performed in a different order than the order shown inSchemes A-C. Various modifications to these synthetic reaction schemesmay be made and will be suggested to one skilled in the art havingreferred to the disclosure contained in this Application. Numbering doesnot necessarily correspond to that of claims or other tables.

In Scheme A, compounds of Formula I are synthesized by activating thecarboxyl group in A-1 to provide aldehyde A-2. In a separate reactionvessel, aryl A-3 is subjected to a metallation reaction to formmetallated aryl A-4. Suitable reagents for carrying out the metallationreaction include, but are not limited to, n-BuLi, sec-BuLi, t-BuLi,t-BuOK, or i-PrMgCl lithium chloride complex, and the like. Suitablesolvents include, but are not limited to, tetrahydrofuran, diethylether, petane, 1,4-dioxane, methyl t-butyl ether, and a mixture thereof.Typically without isolation, metallated aryl A-4 is reacted withcompound A-2 to give alcohol A-5. The reaction is generally carried outat a low temperature, for example, −20 to −100° C. A-5 is then oxidizedto give diaryl ketone A-6. After removing the protecting group in A-6,the anilino nitrogen is derivatized to give target compound of FormulaI. Examples of protecting group include, but are not limited to—C(═O)Ot-Bu and —C(═O)t-Bu. The deprotection can be carried out withstrong acids, such as HCl, HBr, trifluoroaceti acid, and H₂SO₄, orstrong bases, such as NaOH, KOH, or CsOH.

In Scheme B, carboxylic acid B-1 is used as the starting material.Chlorination of B-1 yields acid chloride B-2. Depending upon thesubstituents on the quinoxaline ring, the heteroaryl may be selectivelychlorinated. Following similar procedures as described in Scheme A,aldehyde B-3 is converted to alcohol B-4, which is then oxidized toketone B-5. R₁ group is then introduced under nucleophilic displacementor transition metal catalyzed cross-coupling conditions to give targetFormula I. Examples of nucleophiles under nucleophilic displacementconditions include alcohols, amines, amides, alkylthiols, cyanide,halogen, and heteroaryls. Under the nucleophilic displacementconditions, a strong base may be added to facilitate the transformation.Suitable strong bases include Cs₂CO₃, NaH, KH, t-BuOK, LiH, and CaH₂.Suitable solvents include, but are not limited to, DMF, DMSO, DMA, andN-methyl piperidone. The reaction are generally carried out at atemperature ranging from 25-240° C. Exemplary transition metal catalyzedcross-coupling reactions include, Negishi, Suzuki, Stille and Heckcoupling reactions (see Cross-Coupling Reactions: A Practical Guide,Norio Miyaura et al., Springer; 1^(st) edition 2002, and is hereinincorporated by reference). In a further embodiment, Suzukicross-coupling reaction with aryl, heteroaryl, or alkyl boronic acid orester as nucleophile, in the presence of a base, such as Na₂CO₃, K₂CO₃,Cs₂CO₃, and a Pd catalyst, is used to introduce R₁ group. The reactionis generally carried out at a temperature ranging from 35 to 180° C. ina suitable solvent such as 1,4-dioxane, water, tetrahydrofuran, or amixture thereof.

In Scheme C, the synthesis commences with dihydroquinoxalinone C-1.Chlorination of C-1 yields chloride C-2. R₁ group is introduced at thisstage via a displacement or cross coupling reaction as described inScheme B. The remaining aryl halide in C-3 is converted to a formylgroup via a transition metal catalyzed formylation reaction. Suitableformylation conditions include reacting the substrate in the presence ofCO gas, a reducing reagent, such as a trialkyl silane, an amine base, aPd catalyst and a ligand at a temperature ranging from 40 to 160° C.Reaction of formyl C-4 with A-4 gives alcohol C-5, which yields diarylketone A-5 upon oxidation. As described in Scheme A, A-5 is converted toa compound of Formula I.

C. Pharmaceutical Compositions and Formulations

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. In specific embodiments, pharmaceuticalcompositions are formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Any pharmaceuticallyacceptable techniques, carriers, and excipients are used as suitable toformulate the pharmaceutical compositions described herein: Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound ofFormula I, and a pharmaceutically acceptable diluent(s), excipient(s),or carrier(s). In certain embodiments, the compounds described areadministered as pharmaceutical compositions in which compounds ofFormula I, are mixed with other active ingredients, as in combinationtherapy. Encompassed herein are all combinations of actives set forth inthe combination therapies section below and throughout this disclosure.In specific embodiments, the pharmaceutical compositions include one ormore compounds of Formula I.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula I, with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. In certain embodiments, the pharmaceuticalcomposition facilitates administration of the compound to an organism.In some embodiments, practicing the methods of treatment or use providedherein, therapeutically effective amounts of compounds of Formula I,provided herein are administered in a pharmaceutical composition to amammal having a disease or condition to be treated. In specificembodiments, the mammal is a human. In certain embodiments,therapeutically effective amounts vary depending on the severity of thedisease, the age and relative health of the subject, the potency of thecompound used and other factors. The compounds described herein are usedsingly or in combination with one or more therapeutic agents ascomponents of mixtures.

In one embodiment, one or more compounds of Formula I, is formulated inan aqueous solution. In specific embodiments, the aqueous solution isselected from, by way of example only, a physiologically compatiblebuffer, such as Hank's solution, Ringer's solution, or physiologicalsaline buffer. In other embodiments, one or more compound of Formula I,is formulated for transmucosal administration. In specific embodiments,transmucosal formulations include penetrants that are appropriate to thebarrier to be permeated. In still other embodiments wherein thecompounds described herein are formulated for other parenteralinjections, appropriate formulations include aqueous or nonaqueoussolutions. In specific embodiments, such solutions includephysiologically compatible buffers and/or excipients.

In another embodiment, compounds described herein are formulated fororal administration. Compounds described herein, including compounds ofFormula I, are formulated by combining the active compounds with, e.g.,pharmaceutically acceptable carriers or excipients. In variousembodiments, the compounds described herein are formulated in oraldosage forms that include, by way of example only, tablets, powders,pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries,suspensions and the like.

In certain embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with one or more of thecompounds described herein, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as:for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Inspecific embodiments, disintegrating agents are optionally added.Disintegrating agents include, by way of example only, cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, areprovided with one or more suitable coating. In specific embodiments,concentrated sugar solutions are used for coating the dosage form. Thesugar solutions, optionally contain additional components, such as byway of example only, gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dyestuffs and/orpigments are also optionally added to the coatings for identificationpurposes. Additionally, the dyestuffs and/or pigments are optionallyutilized to characterize different combinations of active compounddoses.

In certain embodiments, therapeutically effective amounts of at leastone of the compounds described herein are formulated into other oraldosage forms. Oral dosage forms include push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. In specific embodiments,push-fit capsules contain the active ingredients in admixture with oneor more filler. Fillers include, by way of example only, lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In other embodiments, softcapsules, contain one or more active compound that is dissolved orsuspended in a suitable liquid. Suitable liquids include, by way ofexample only, one or more fatty oil, liquid paraffin, or liquidpolyethylene glycol. In addition, stabilizers are optionally added.

In other embodiments, therapeutically effective amounts of at least oneof the compounds described herein are formulated for buccal orsublingual administration. Formulations suitable for buccal orsublingual administration include, by way of example only, tablets,lozenges, or gels. In still other embodiments, the compounds describedherein are formulated for parental injection, including formulationssuitable for bolus injection or continuous infusion. In specificembodiments, formulations for injection are presented in unit dosageform (e.g., in ampoules) or in multi-dose containers. Preservatives are,optionally, added to the injection formulations. In still otherembodiments, the pharmaceutical composition of a compound of Formula Iis formulated in a form suitable for parenteral injection as sterilesuspension, solution or emulsion in oily or aqueous vehicles. Parenteralinjection formulations optionally contain formulatory agents such assuspending, stabilizing and/or dispersing agents. In specificembodiments, pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.In additional embodiments, suspensions of the active compounds areprepared as appropriate oily injection suspensions. Suitable lipophilicsolvents or vehicles for use in the pharmaceutical compositionsdescribed herein include, by way of example only, fatty oils such assesame oil, or synthetic fatty acid esters, such as ethyl oleate ortriglycerides, or liposomes. In certain specific embodiments, aqueousinjection suspensions contain substances which increase the viscosity ofthe suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension contains suitable stabilizers oragents which increase the solubility of the compounds to allow for thepreparation of highly concentrated solutions. Alternatively, in otherembodiments, the active ingredient is in powder form for constitutionwith a suitable vehicle, e.g., sterile pyrogen-free water, before use.

In still other embodiments, the compounds of Formula I are administeredtopically. The compounds described herein are formulated into a varietyof topically administrable compositions, such as solutions, suspensions,lotions, gels, pastes, medicated sticks, balms, creams or ointments.Such pharmaceutical compositions optionally contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

In yet other embodiments, the compounds of Formula I are formulated fortransdermal administration. In specific embodiments, transdermalformulations employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Invarious embodiments, such patches are constructed for continuous,pulsatile, or on demand delivery of pharmaceutical agents. In additionalembodiments, the transdermal delivery of the compounds of Formula I, isaccomplished by means of iontophoretic patches and the like. In certainembodiments, transdermal patches provide controlled delivery of thecompounds of Formula I. In specific embodiments, the rate of absorptionis slowed by using rate-controlling membranes or by trapping thecompound within a polymer matrix or gel. In alternative embodiments,absorption enhancers are used to increase absorption. Absorptionenhancers or carriers include absorbable pharmaceutically acceptablesolvents that assist passage through the skin. For example, in oneembodiment, transdermal devices are in the form of a bandage comprisinga backing member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundto the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

In other embodiments, the compounds of Formula I, are formulated foradministration by inhalation. Various forms suitable for administrationby inhalation include, but are not limited to, aerosols, mists orpowders. Pharmaceutical compositions of Formula I, are convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebuliser, with the use of a suitable propellant (e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas). Inspecific embodiments, the dosage unit of a pressurized aerosol isdetermined by providing a valve to deliver a metered amount. In certainembodiments, capsules and cartridges of, such as, by way of exampleonly, gelatin for use in an inhaler or insufflator are formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

In still other embodiments, the compounds of Formula I, are formulatedin rectal compositions such as enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, or retention enemas,containing conventional suppository bases such as cocoa butter or otherglycerides, as well as synthetic polymers such as polyvinylpyrrolidone,PEG, and the like. In suppository forms of the compositions, alow-melting wax such as, but not limited to, a mixture of fatty acidglycerides, optionally in combination with cocoa butter is first melted.

In certain embodiments, pharmaceutical compositions are formulated inany conventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients are optionally used as suitable. Pharmaceuticalcompositions comprising a compound of Formula I, are manufactured in aconventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

Pharmaceutical compositions include at least one pharmaceuticallyacceptable carrier, diluent or excipient and at least one compound ofFormula I, described herein as an active ingredient. The activeingredient is in free-acid or free-base form, or in a pharmaceuticallyacceptable salt form. In addition, the methods and pharmaceuticalcompositions described herein include the use of N-oxides, crystallineforms (also known as polymorphs), as well as active metabolites of thesecompounds having the same type of activity. All tautomers of thecompounds described herein are included within the scope of thecompounds presented herein. Additionally, the compounds described hereinencompass unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein. In addition, the pharmaceutical compositionsoptionally include other medicinal or pharmaceutical agents, carriers,adjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressure,buffers, and/or other therapeutically valuable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The form of the pharmaceuticalcompositions described herein include liquid solutions or suspensions,solid forms suitable for solution or suspension in a liquid prior touse, or as emulsions. These compositions also optionally contain minoramounts of nontoxic, auxiliary substances, such as wetting oremulsifying agents, pH buffering agents, and so forth.

In some embodiments, a pharmaceutical composition comprising at leastone compound of Formula I, illustratively takes the form of a liquidwhere the agents are present in solution, in suspension or both.Typically when the composition is administered as a solution orsuspension a first portion of the agent is present in solution and asecond portion of the agent is present in particulate form, insuspension in a liquid matrix. In some embodiments, a liquid compositionincludes a gel formulation. In other embodiments, the liquid compositionis aqueous.

In certain embodiments, useful aqueous suspension contain one or morepolymers as suspending agents. Useful polymers include water-solublepolymers such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linkedcarboxyl-containing polymers. Certain pharmaceutical compositionsdescribed herein comprise a mucoadhesive polymer, selected for examplefrom carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Useful pharmaceutical compositions also, optionally, includesolubilizing agents to aid in the solubility of a compound of Formula I.The term “solubilizing agent” generally includes agents that result information of a micellar solution or a true solution of the agent.Certain acceptable nonionic surfactants, for example polysorbate 80, areuseful as solubilizing agents, as can ophthalmically acceptable glycols,polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

Furthermore, useful pharmaceutical compositions optionally include oneor more pH adjusting agents or buffering agents, including acids such asacetic, boric, citric, lactic, phosphoric and hydrochloric acids; basessuch as sodium hydroxide, sodium phosphate, sodium borate, sodiumcitrate, sodium acetate, sodium lactate andtris-hydroxymethylaminomethane; and buffers such as citrate/dextrose,sodium bicarbonate and ammonium chloride. Such acids, bases and buffersare included in an amount required to maintain pH of the composition inan acceptable range.

Additionally, useful compositions also, optionally, include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Other useful pharmaceutical compositions optionally include one or morepreservatives to inhibit microbial activity. Suitable preservativesinclude mercury-containing substances such as merfen and thiomersal;stabilized chlorine dioxide; and quaternary ammonium compounds such asbenzalkonium chloride, cetyltrimethylammonium bromide andcetylpyridinium chloride.

Still other useful compositions include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Still other useful compositions include one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

In certain embodiments, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. Alternatively, multiple-dosereclosable containers are used, in which case it is typical to include apreservative in the composition.

In alternative embodiments, other delivery systems for hydrophobicpharmaceutical compounds are employed. Liposomes and emulsions areexamples of delivery vehicles or carriers useful herein. In certainembodiments, organic solvents such as N-methylpyrrolidone are alsoemployed. In additional embodiments, the compounds described herein aredelivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials are useful herein. In someembodiments, sustained-release capsules release the compounds for a fewweeks up to over 100 days. Depending on the chemical nature and thebiological stability of the therapeutic reagent, additional strategiesfor protein stabilization are employed.

In certain embodiments, the formulations described herein comprise oneor more antioxidants, metal chelating agents, thiol containing compoundsand/or other general stabilizing agents. Examples of such stabilizingagents, include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

D. Routes of Administration

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. In such embodiments, the liposomes are targetedto and taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

E. Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also provided. In some embodiments, suchkits comprise a carrier, package, or container that is compartmentalizedto receive one or more containers such as vials, tubes, and the like,each of the container(s) comprising one of the separate elements to beused in a method described herein. Suitable containers include, forexample, bottles, vials, syringes, and test tubes. The containers areformed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products Includethose found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.For example, the container(s) includes one or more compounds describedherein, optionally in a composition or in combination with another agentas disclosed herein. The container(s) optionally have a sterile accessport (for example the container is an intravenous solution bag or a vialhaving a stopper pierceable by a hypodermic injection needle). Such kitsoptionally comprising a compound with an identifying description orlabel or instructions relating to its use in the methods describedherein.

For example, a kit typically includes one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for use of a compound described herein. Non-limitingexamples of such materials include, but not limited to, buffers,diluents, filters, needles, syringes; carrier, package, container, vialand/or tube labels listing contents and/or instructions for use, andpackage inserts with instructions for use. A set of instructions willalso typically be included. A label is optionally on or associated withthe container. For example, a label is on a container when letters,numbers or other characters forming the label are attached, molded oretched into the container itself, a label is associated with a containerwhen it is present within a receptacle or carrier that also holds thecontainer, e.g., as a package insert. In addition, a label is used toindicate that the contents are to be used for a specific therapeuticapplication. In addition, the label indicates directions for use of thecontents, such as in the methods described herein. In certainembodiments, the pharmaceutical compositions is presented in a pack ordispenser device which contains one or more unit dosage forms containinga compound provided herein. The pack for example contains metal orplastic foil, such as a blister pack. Or, the pack or dispenser deviceis accompanied by instructions for administration. Or, the pack ordispenser is accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, is the labeling approved bythe U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. In some embodiments, Compositions containing acompound provided herein formulated in a compatible pharmaceuticalcarrier are prepared, placed in an appropriate container, and labeledfor treatment of an indicated condition.

F. Methods of Use

The chemical entities described herein are useful in the treatment, orin the preparation of a medicament for the treatment of variousdisorders. For example, compounds of Formula I are useful as inhibitorsof protein kinases. In some embodiments, the chemical entities describedherein are inhibitors of one or more kinases. For example, compounds ofFormula I are inhibitors of A-Raf, B-Raf, C-Raf, and of mutants of suchkinases, including the B-Raf V600E mutant. Thus, without wishing to bebound by any particular theory, the compounds of Formula I areparticularly useful for treating or lessening the severity of a disease,condition, or disorder where activation of one or more kinases, such asRaf kinases, which is implicated in the disease, condition, or disorder.When activation of Raf kinases is implicated in a particular disease,condition, or disorder, the disease, condition, or disorder may also bereferred to as “Raf-mediated disease” or disease symptom. Accordingly,in another aspect, the present invention provides a method for treatingor lessening the severity of a disease, condition, or disorder whereactivation or one or more of Raf kinases is implicated in the diseasestate.

The inhibition of kinases may be assayed in vitro, in vivo or in a cellline. In vitro assays include assays that determine inhibition of eitherthe phosphorylation activity or ATPase activity of activated kinase.Alternate in vitro assays quantitate the ability of the inhibitor tobind to kinase. Inhibitor binding may be measured by radiolabelling theinhibitor prior to binding, isolating the inhibitor, complex anddetermining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with kinase bound to known radioligands. At 1micro-molar concentration, one or more compounds of the presentinvention exhibits at least about 50%, 60%, 70, 80%, 90% or even higherinhibition of kinases including B-Raf, and B-Raf V600E mutant.

The chemical entities described herein may be prepared in substantiallypure form, typically by standard chromatographic methods, prior toformulation in a pharmaceutically acceptable form.

The chemical entities described herein may be used in treating a varietyof cancers. Cancers that can be prevented and/or treated by the chemicalentities, compositions, and methods described herein include, but arenot limited to, human sarcomas and carcinomas, e.g. carcinomas, e.g.,colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer,prostate cancer, thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonalcarcinoma, Wilms' tumor, cervical cancer, testicular tumor, lungcarcinoma, small cell lung carcinoma, bladder carcinoma, epithelialcarcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma,ependymoma, pinealoma, hemangioblastoma, acoustic neuroma,oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma,leukemias, e.g., acute lymphocytic leukemia and acute myelocyticleukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic anderythroleukemia); chronic leukemia (chronic myelocytic (granulocytic)leukemia and chronic lymphocytic leukemia); and polycythemia vera,lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiplemyeloma, Waldenstrom's macroglobulinemia, and heavy chain disease.

In some embodiments, the chemical entities described herein are used forthe treatment of cancers of the

-   -   i. digestive system including, without limitation, the        esophagus, stomach, small intestine, colon (including        colorectal), liver & intrahepatic bile duct, gallbladder & other        biliary, pancreas, and other digestive organs;    -   ii. respiratory system, including without limitation, larynx,        lung & bronchus, and other respiratory organs;    -   iii. skin;    -   iv. thyroid;    -   v. breast;    -   vi. genital system, including without limitation, uterine        cervix, ovary, and prostate;    -   vii. urinary system, including without limitation, urinary        bladder and kidney and renal pelvis; and    -   viii. oral cavity & pharynx, including without limitation,        tongue, mouth, pharynx, and other oral cavity.

In some embodiments, the chemical entities described herein are used forthe treatment of colon cancer, liver cancer, lung cancer, melanoma,thyroid cancer, breast cancer, ovarian cancer, and oral cancer.

The chemical entities described herein may also be used in conjunctionwith other well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated. Forexample, the chemical entities described herein may be useful incombination with at least one additional anti-cancer and/or cytotoxicagents. Further, the chemical entities described herein may also beuseful in combination with other inhibitors of parts of the signalingpathway that links cell surface growth factor receptors to nuclearsignals initiating cellular proliferation.

Such known anti-cancer and/or cytotoxic agents that may be used incombination with the chemical entities described herein include:

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumorantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycinC,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5a-reductase suchas finasteride;

(iii) anti-invasion agents [for example c-Src kinase family inhibitorslike4-(6-chloro-2,3methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4yloxyquinazoline(AZD0530; International Patent Application WO 01/94341),N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 66586661) and bosutinib(SK1-606), and metalloproteinase inhibitors like marimastat, inhibitorsof urokinase plasminogen activator receptor function or antibodies toHeparanase];

(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB 1 antibody cetuximab[Erbitux, C225] and any growth factor or growth factor receptorantibodies disclosed by Stem et al. Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);inhibitors of the hepatocyte growth factor family; inhibitors of theinsulin growth factor family; inhibitors of the platelet-derived growthfactor family such as imatinib and/or nilotinib (AMN107); inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas famesyl transferase inhibitors, for example sorafenib (BAY 43-9006),tipifamib (RI15777) and lonafamib (SCH66336)), inhibitors of cellsignalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinaseinhibitors, P13 kinase inhibitors, Plt3 kinase inhibitors, CSF-IR kinaseinhibitors, IGF receptor (insulin like growth factor) kinase inhibitors;aurora kinase inhibitors (for example AZD1152, PH739358, VX-680,MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin dependentkinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and forexample, a VEGF receptor tyrosine kinase inhibitor such as vandetanib(ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736),pazopanib (GW 786034) and4.{4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3pyrrolidin-1-ylpropoxy)quinazoline(AZD2171; Example 240 within WO 00/47212), compounds such as thosedisclosed in International Patent Applications WO 97/22596, WO 97/30035,WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms(for example linomide, inhibitors of integrin av˜3 function andangiostatin));

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054)or atrasentan;

(viii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;

(ix) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase subject tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and

(x) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of subject's tumor cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell energy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumor cell lines and approaches usinganti-idiotypic antibodies.

In certain embodiments, the at least one chemical entity is administeredin combination with one or more agents chosen from pacliataxel,bortezomib, dacarbazine, gemcitabine, trastuzumab, bevacizumab,capecitabine, docetaxel, erlotinib, aromatase inhibitors, such asAROMASIN™ (exemestane), and estrogen receptor inhibitors, such asFASLODEX™ (fulvestrant).

When a chemical entity described herein is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual subject, as well as the severityof the subject's symptoms.

In one exemplary application, a suitable amount of at least one chemicalentity is administered to a mammal undergoing treatment for cancer, forexample, breast cancer. Administration typically occurs in an amount ofbetween about 0.01 mg/kg of body weight to about 100 mg/kg of bodyweight per day (administered in single or divided doses), such as atleast about 0.1 mg/kg of body weight per day. A particular therapeuticdosage can include, e.g., from about 0.01 mg to about 1000 mg of thechemical entity, such as including, e.g., from about 1 mg to about 1000mg. The quantity of the at least one chemical entity in a unit dose ofpreparation may be varied or adjusted from about 0.1 mg to 1000 mg, suchas from about 1 mg to 300 mg, for example 10 mg to 200 mg, according tothe particular application. The amount administered will vary dependingon the particular IC₅₀ value of the at least one chemical entity usedand the judgment of the attending clinician taking into considerationfactors such as health, weight, and age. In combinational applicationsin which the at least one chemical entity described herein is not thesole active ingredient, it may be possible to administer lesser amountsof the at least one chemical entity and still have therapeutic orprophylactic effect.

In some embodiments, the pharmaceutical preparation is in unit dosageform. In such form, the preparation is subdivided into unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The actual dosage employed may be varied depending upon the requirementsof the subject and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the at least onechemical entity. Thereafter, the dosage is increased by small amountsuntil the optimum effect under the circumstances is reached. Forconvenience, the total daily dosage may be divided and administered inportions during the day if desired.

The amount and frequency of administration of the at least one chemicalentities described herein, and if applicable other chemotherapeuticagents and/or radiation therapy, will be regulated according to thejudgment of the attending clinician (physician) considering such factorsas age, condition and size of the subject as well as severity of thedisease being treated.

The chemotherapeutic agent and/or radiation therapy can be administeredaccording to therapeutic protocols well known in the art. It will beapparent to those skilled in the art that the administration of thechemotherapeutic agent and/or radiation therapy can be varied dependingon the disease being treated and the known effects of thechemotherapeutic agent and/or radiation therapy on that disease. Also,in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., antineoplastic agent or radiation) on thesubject, and in view of the observed responses of the disease to theadministered therapeutic agents.

Also, in general, the at least one chemical entities described hereinneed not be administered in the same pharmaceutical composition as achemotherapeutic agent, and may, because of different physical andchemical characteristics, be administered by a different route. Forexample, the chemical entities/compositions may be administered orallyto generate and maintain good blood levels thereof, while thechemotherapeutic agent may be administered intravenously. Thedetermination of the mode of administration and the advisability ofadministration, where possible, in the same pharmaceutical composition,is well within the knowledge of the skilled clinician. The initialadministration can be made according to established protocols known inthe art, and then, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician.

The particular choice of chemical entity (and where appropriate,chemotherapeutic agent and/or radiation) will depend upon the diagnosisof the attending physicians and their judgment of the condition of thesubject and the appropriate treatment protocol.

The chemical entities described herein (and where appropriatechemotherapeutic agent and/or radiation) may be administeredconcurrently (e.g., simultaneously, essentially simultaneously or withinthe same treatment protocol) or sequentially, depending upon the natureof the proliferative disease, the condition of the subject, and theactual choice of chemotherapeutic agent and/or radiation to beadministered in conjunction (i.e., within a single treatment protocol)with the chemical entity/composition.

In combinational applications and uses, the chemical entity/compositionand the chemotherapeutic agent and/or radiation need not be administeredsimultaneously or essentially simultaneously, and the initial order ofadministration of the chemical entity/composition, and thechemotherapeutic agent and/or radiation, may not be important. Thus, theat least one chemical entity described herein may be administered firstfollowed by the administration of the chemotherapeutic agent and/orradiation; or the chemotherapeutic agent and/or radiation may beadministered first followed by the administration of the at least onechemical entity described herein. This alternate administration may berepeated during a single treatment protocol. The determination of theorder of administration, and the number of repetitions of administrationof each therapeutic agent during a treatment protocol, is well withinthe knowledge of the skilled physician after evaluation of the diseasebeing treated and the condition of the subject. For example, thechemotherapeutic agent and/or radiation may be administered first, andthen the treatment continued with the administration of the at least onechemical entity described herein followed, where determinedadvantageous, by the administration of the chemotherapeutic agent and/orradiation, and so on until the treatment protocol is complete.

Thus, in accordance with experience and knowledge, the practicingphysician can modify each protocol for the administration of a chemicalentity/composition for treatment according to the individual subject'sneeds, as the treatment proceeds.

The attending clinician, in judging whether treatment is effective atthe dosage administered, will consider the general well-being of thesubject as well as more definite signs such as relief of disease-relatedsymptoms, inhibition of tumor growth, actual shrinkage of the tumor, orinhibition of metastasis. Size of the tumor can be measured by standardmethods such as radiological studies, e.g., CAT or MRI scan, andsuccessive measurements can be used to judge whether or not growth ofthe tumor has been retarded or even reversed. Relief of disease-relatedsymptoms such as pain, and improvement in overall condition can also beused to help judge effectiveness of treatment.

EXAMPLES

The following examples serve to more fully describe the manner of usingthe invention. These examples are presented for illustrative purposesand should not serve to limit the true scope of the invention.

In carrying out the procedures of the methods described herein, it is ofcourse to be understood that reference to particular buffers, media,reagents, cells, culture conditions and the like are not intended to belimiting, but are to be read so as to include all related materials thatone of ordinary skill in the art would recognize as being of interest orvalue in the particular context in which that discussion is presented.For example, it is often possible to substitute one buffer system orculture medium for another and still achieve similar, if not identical,results. Those of skill in the art will have sufficient knowledge ofsuch systems and methodologies so as to be able, without undueexperimentation, to make such substitutions as will optimally servetheir purposes in using the methods and procedures disclosed herein.

Example 1: Preparation of1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

To a solution of quinoxalin-2(1H)-one (54.64 g, 374 mmol, 1.0 eq.) inHOAc (1000 mL) was added a solution of Br₂ (19.18 mL, 374 mmol, 1.0 eq.)in HOAc (200 mL) dropwise. The resulting mixture was stirred at r.t. for12 h, then poured into ice-water. The precipitate was collected byfiltration and dried to afford 7-bromoquinoxalin-2(1H)-one as anoff-white solid (74 g, 88% yield).

To a suspension of 7-bromoquinoxalin-2(1H)-one (224 g, 1 mol, 1.0 eq.)in POCl₃ (1000 mL) was added DMF (3.65 g, 0.05 mol, 0.05 eq.). Theresulting mixture was stirred at 120° C. for 2 h, then cooled to r.t.and slowly poured into ice-water with vigorous stirring. The precipitatewas collected by filtration and dried to afford7-bromo-2-chloroquinoxaline as a brown solid (180 g, 75% yield).

To a solution of 7-bromo-2-chloroquinoxaline (50 g, 0.2 mol, 1.0 eq.) inCH₃CN (200 mL) were added morpholine (89 g, 1.02 mol, 5.0 eq.) and K₂CO₃(85 g, 0.61 mol, 3.0 eq.). The resulting mixture was stirred at 90° C.for 2 h, then cooled and filtered. The filtrate was concentrated and theresulting residue was recrystallized from ethyl acetate to afford4-(7-bromoquinoxalin-2-yl)morpholine (59 g, 98.3% yield).

To a solution of 4-(7-bromoquinoxalin-2-yl)morpholine (59 g, 0.2 mol,1.0 eq.) in DMF (500 mL) was added TEA (139 mL, 1.0 mol, 5.0 eq.),Et₃SiH (127 mL, 0.8 mol, 4.0 eq) and Pd(dppf)Cl₂CH₂Cl₂ (8.16 g, 0.01mol, 0.05 eq.). The resulting mixture was stirred at 90° C. in anautoclave for 12 h under CO (1 MPa), then cooled and concentrated. Theresulting residue was purified via flash column chromatography(EA/PE=1/1, v/v) to afford 3-morpholinoquinoxaline-6-carbaldehyde as ayellow solid (40 g, 82.3% yield).

To a solution of N-(4-bromophenyl)pivalamide (2.56 g, 10 mmol, 1.0 eq.)in THF (80 mL) cooled at −78° C. was added n-BuLi (8 mL, 20 mmol, 2.0eq.) dropwise. The mixture was stirred at −78° C. for 30 min, then asolution of 3-morpholinoquinoxaline-6-carbaldehyde (2.34 g, 10 mmol, 1.0eq.) in THF (70 mL) was added dropwise. The mixture was stirred at −78°C. for 1 h, then quenched by the addition of aqueous NH₄Cl solution. Themixture was extracted with EA (50 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated. The resulting residuewas purified via flash column chromagraphy (PE/EA=1/1, v/v) to affordN-(4-(hydroxy(3-morpholinoquinoxalin-6-yl)methyl)phenyl)pivalamide (800mg, 19.8% yield).

To a solution ofN-(4-(hydroxy(3-morpholinoquinoxalin-6-yl)methyl)phenyl)pivalamide (1.17g, 2.8 mmol, 1.0 eq.) in DCM (25 mL) was added MnO₂ (1.2 g, 13.9 mmol,5.0 eq.). The resulting mixture was stirred at 50° C. overnight, thencooled and filtered. The filtrate was concentrated and the residue waspurified via flash column chromatography (PE/EA=1/1, v/v) to affordN-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)pivalamide (350 mg,30.1% yield).

To a solution ofN-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)pivalamide (350 mg, 0.84mmol, 1.0 eq.) in HOAc (6 mL) was added conc. HCl (3 mL). The mixturewas stirred at 110° C. for 4 h, then poured onto ice. The mixture wasadjusted to pH=10 by the addition of 1N NaOH aqueous solution, thenextracted with DCM (20 mL×3). The combined organic layers were driedover Na₂SO₄ and concentrated. The resulting residue was purified viaflash column chromatography (PE/EA=1/1, v/v) to afford(4-aminophenyl)(3-morpholinoquinoxalin-6-yl)methanone as a yellow solid(280 mg, quant. yield).

To a solution of (4-aminophenyl)(3-morpholinoquinoxalin-6-yl)methanone(80 mg, 0.27 mmol, 1.0 eq.) in DCM (5 mL) were added TEA (0.2 mL, 1.35mmol, 5.0 eq.) and 1-fluoro-3-isocyanatobenzene (70 mg, 0.54 mmol, 2eq.). The mixture was stirred at r.t. for 1 h, and concentrated. Theresulting residue was purified via flash column chromatography(PE/EA=2/1, v/v) to afford1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea(27.0 mg, 21.6% yield) LRMS (M+H⁺) m/z calculated 522.2, found 522.2. ¹HNMR (DMSO-d6, 400 MHz) δ 9.32 (s, 1H), 9.28 (s, 1H), 8.95 (s, 1H), 7.99(d, 1H), 7.80-7.82 (m, 3H), 7.65-7.72 (m, 7H), 3.73 (d, 8H).

Example 2: Preparation of1-(3-chlorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(3-chlorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(3-Chlorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea(26.5 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H+) m/z calculated 488.1, found 488.2. ¹H NMR (DMSO-d6, 300 MHz)δ 9.27 (s, 1H), 9.05 (s, 1H), 8.94 (s, 1H), 7.98 (d, 1H), 7.80 (d, 3H),7.64-7.73 (m, 4H), 7.31-7.36 (m, 2H), 7.04-7.07 (m, 1H), 3.76 (s, 8H).

Example 3: Preparation of1-(4-chlorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-chlorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-Chlorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea(20.2 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+^(H)) m/z calculated 488.1, found 488.1. ¹H NMR (DMSO-d6, 400MHz) δ 9.22 (s, 1H), 8.96 (d, 2H), 7.98 (d, 1H), 7.78-7.82 (m, 3H),7.64-7.71 (m, 3H), 7.51 (d, 2H), 7.35 (d, 2H), 3.77 (d, 8H).

Example 4: Preparation of1-(4-fluorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-fluorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-Fluorophenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea(29.5 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 472.2, found 472.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.18 (s, 1H), 8.94 (s, 1H), 8.87 (s, 1H), 7.98 (d, 1H), 7.78-7.82 (m,3H), 7.64-7.71 (m, 3H), 7.46-7.51 (m, 2H), 7.15 (t, 2H), 3.77 (d, 8H).

Example 5: Preparation of1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea(21.4 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 540.2, found 540.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.33 (s, 1H), 9.20 (s, 1H), 8.94 (s, 1H), 7.97-8.03 (m, 2H), 7.79-7.82(m, 3H), 7.66-7.71 (m, 4H), 7.46 (t, 1H), 3.72-3.77 (m, 4H).

Example 6: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea(18.7 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 556.1, found 554.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.34 (d, 2H), 8.94 (s, 1H), 8.13 (s, 1H), 7.98 (d, 1H), 7.77-7.82 (m,3H), 7.63-7.71 (m, 5H), 3.74 (d, 8H).

Example 7: Preparation of1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea(44 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 547.2, found 547.3. ¹H NMR (DMSO-d6, 400 MHz)δ 9.75 (s, 1H), 9.55 (s, 1H), 8.95 (s, 1H), 8.24 (s, 1H), 8.07 (d, 1H),7.99 (d, 1H), 7.81-7.83 (m, 4H), 7.68-7.72 (m, 3H), 3.76-3.77 (m, 8H).

Example 8: Preparation of1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea(40.1 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 565.2, found 565.2. ¹H NMR (DMSO-d6, 300 MHz)δ 9.85 (s, 1H), 9.71 (s, 1H), 8.95 (s, 1H), 8.23 (s, 1H), 8.09 (d, 1H),7.97 (d, 1H), 7.61-7.85 (m, 5H), 7.39-7.41 (m, 1H), 3.71-3.81 (m, 8H).

Example 9: Preparation of1-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea

1-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea

1-(3-Fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea(44.6 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 490.2, found 490.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.41 (s, 1H), 9.17 (s, 1H), 8.94 (s, 1H), 7.18-7.98 (m, 9H), 6.84 (t,1H), 3.75-3.77 (m, 8H).

Example 10: Preparation of1-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea

1-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea

1-(3-Fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea(23.6 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 490.2, found 490.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.35 (s, 1H), 8.94-8.97 (m, 2H), 7.97 (d, 1H), 7.83 (s, 1H), 7.49-7.77(m, 5H), 7.31 (d, 1H), 7.16 (t, 2H), 3.75-3.77 (m, 8H).

Example 11: Preparation of1-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(3-Fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(24.9 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 540.2, found 540.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.46 (s, 1H), 9.29 (s, 1H), 8.94 (s, 1H), 7.96-8.03 (m, 3H), 7.55-7.83(m, 6H), 7.35 (t, 1H), 3.75-3.76 (m, 8H).

Example 12: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea(21.8 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 574.1, found 574.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.51 (s, 1H), 9.41 (s, 1H), 8.94 (s, 1H), 8.12 (s, 1H), 7.97 (d, 2H),7.62-7.83 (m, 6H), 7.36 (d, 1H), 3.75-3.76 (m, 8H).

Example 13: Preparation of1-(4-(quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-(quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-(Quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(30.9 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 437.1, found 437.1. ¹H NMR (DMSO-d6, 400 MHz)δ 9.39 (s, 1H), 9.26 (s, 1H), 9.09 (s, 2H), 8.33 (s, 1H), 8.27 (d, 1H),8.15 (dd, 1H), 8.04 (s, 1H), 7.86 (d, 2H), 7.70 (d, 2H), 7.62 (d, 1H),7.54-7.57 (m, 1H), 7.35 (d, 1H).

Example 14: Preparation of1-(3-fluorophenyl)-3-(4-(quinoxaline-6-carbonyl)phenyl)urea

1-(3-fluorophenyl)-3-(4-(quinoxaline-6-carbonyl)phenyl)urea

1-(3-Fluorophenyl)-3-(4-(quinoxaline-6-carbonyl)phenyl)urea (42.1 mg)was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 387.1, found 387.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.30 (s, 1H), 9.09 (s, 3H), 8.33 (s, 1H), 8.27 (d, 1H), 8.15 (dd, 1H),7.86 (d, 2H), 7.68 (d, 2H), 7.48-7.52 (m, 1H), 7.31-7.36 (m, 1H),7.15-7.18 (m, 1H), 6.80-6.85 (m, 1H).

Example 15: Preparation of1-(4-chlorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-chlorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-Chlorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea(31.8 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 487.2, found 487.2. ¹H NMR (DMSO-d6, 300 MHz)δ 9.25 (s, 1H), 9.01 (s, 1H), 8.92 (s, 1H), 7.94 (d, 1H), 7.78-7.81 (m,3H), 7.64-7.67 (m, 3H), 7.40-7.53 (d, 2H), 7.34-7.37 (d, 2H), 3.71-3.72(m, 4H), 2.80-2.82 (m, 4H).

Example 16: Preparation of1-(4-fluorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-fluorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-Fluorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea(8 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 471.2, found 471.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.48 (s, 1H), 9.16 (s, 1H), 8.92 (s, 1H), 7.95 (d, 1H), 7.78-7.80 (m,3H), 7.64-7.68 (m, 3H), 7.48-7.51 (m, 2H), 7.14 (t, 2H), 3.75 (t, 4H),2.86 (t, 4H).

Example 17: Preparation of1-(3-chlorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(3-chlorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(3-Chlorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea(6.3 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H+) m/z calculated 487.2, found 487.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.41 (s, 1H), 9.21 (s, 1H), 8.93 (s, 1H), 7.96 (d, 1H), 7.79 (d, 3H),7.65-7.73 (m, 4H), 7.31-7.33 (m, 2H), 7.04-7.07 (m, 1H), 3.79 (t, 4H),2.92 (t, 4H).

Example 18: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea(31 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 555.1, found 555.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.40-9.49 (m, 2H), 8.92 (s, 1H), 8.14 (d, 1H), 7.95 (d, 1H), 7.79-7.81(m, 3H), 7.65-7.69 (m, 5H), 3.73 (t, 4H), 2.82 (s, 4H).

Example 19: Preparation of1-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

1-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

1-(4-(3-(Piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea(23.6 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 521.2, found 521.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.35 (s, 1H), 9.30 (s, 1H), 8.93 (s, 1H), 7.96 (d, 1H), 7.79-7.82 (m,3H), 7.65-7.71 (m, 7H), 3.74 (t, 4H), 2.85 (t, 4H).

Example 20: Preparation of1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea(61 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 539.2, found 539.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.47 (s, 1H), 9.34 (s, 1H), 8.93 (s, 1H), 7.94-8.04 (m, 2H), 7.78-7.80(m, 3H), 7.67-7.69 (m, 4H), 7.47 (t, 1H), 3.74 (s, 4H), 2.85 (m, 4H).

Example 21: Preparation of1-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-(3-(Piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(49 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 521.2, found 521.3. ¹H NMR (DMSO-d6, 400 MHz)δ 9.38 (s, 1H), 9.28 (s, 1H), 8.92 (s, 1H), 8.04 (s, 1H), 7.95 (d, 1H),7.79-7.81 (m, 3H), 7.61-7.69 (m, 4H), 7.54 (m, 1H), 7.35 (d, 1H), 3.73(m, 4H), 2.83 (m, 4H).

Example 22: Preparation of1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea(39.4 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 546.2, found 546.3. ¹H NMR (DMSO-d6, 300 MHz)δ 9.81 (s, 1H), 9.61 (s, 1H), 8.92 (s, 1H), 8.24 (s, 1H), 8.06 (d, 1H),7.95 (d, 1H), 7.79-7.83 (m, 4H), 7.66-7.71 (m, 3H), 3.73 (m, 4H), 2.83(m, 4H).

Example 23: Preparation of1-(3-fluorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(3-fluorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(3-Fluorophenyl)-3-(4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea(21.9 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 471.2, found 471.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.37 (s, 1H), 9.19 (s, 1H), 8.92 (s, 1H), 7.95 (d, 1H), 7.66-7.80 (m,6H), 7.52 (d, 1H), 7.33-7.35 (m, 1H), 7.17-7.19 (m, 1H), 6.83 (m, 1H),3.74 (m, 4H), 2.85 (m, 4H).

Example 24: Preparation of1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea

1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea

1-(3-Fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea(47 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 489.2, found 489.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.53 (s, 1H), 9.28 (s, 1H), 8.93 (s, 1H), 7.94 (d, 1H), 7.80 (s, 1H),7.18-7.74 (m, 7H), 6.84 (t, 1H), 3.71-3.74 (m, 4H), 2.82-2.84 (m, 4H).

Example 25: Preparation of1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(3-Fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(53.6 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 539.2, found 539.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.69 (s, 1H), 9.53 (s, 1H), 8.93 (s, 1H), 8.05 (s, 1H), 7.95 (d, 1H),7.55-7.81 (m, 6H), 7.35-7.37 (m, 2H), 3.74-3.76 (m, 4H), 2.86-2.88 (m,4H).

Example 26: Preparation of1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea(32 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 564.2, found 564.2. ¹H NMR (DMSO-d6, 400 MHz)δ 9.82-9.99 (m, 2H), 8.92 (s, 1H), 8.24 (s, 1H), 8.07 (d, 1H), 7.61-7.96(m, 6H), 7.37 (d, 1H), 3.72-3.76 (m, 4H), 2.81-2.85 (m, 4H).

Example 27: Preparation of1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)urea

1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)urea

1-(3-Fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)urea(9.4 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 475.2, found 475.1. ¹H NMR. (CD3OD, 400 MHz)δ 8.66 (s, 1H), 7.79-7.84 (m, 2H), 7.66-7.69 (m, 2H), 7.45-7.52 (m, 2H),7.35 (s, 1H), 7.13 (dd, 1H), 3.76 (s, 3H), 3.72 (t, 4H), 2.87 (t, 4H).

Example 28: Preparation of1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(1-methyl-1H-pyrazol-3-yl)urea

1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(1-methyl-1H-pyrazol-3-yl)urea

1-(3-Fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(1-methyl-1H-pyrazol-3-yl)urea(21.7 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 475.2, found 475.1. ¹H NMR. (CD3OD, 400 MHz)δ 8.77 (s, 1H), 8.00 (t, 1H), 7.92 (d, 1H), 7.81 (dd, 1H), 7.67 (dd,1H), 7.59 (t, 1H), 7.48 (d, 1H), 7.24-7.27 (dd, 1H), 6.24 (brs, 1H),3.84-3.87 (m, 7H), 3.01-3.04 (m, 4H).

Example 29: Preparation of1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(5-methylisoxazol-3-yl)urea

1-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(5-methylisoxazol-3-yl)urea

1-(3-Fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(5-methylisoxazol-3-yl)urea(14 mg) was prepared as described for1-(4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 476.2, found 476.1. ¹H NMR. (CD3OD, 400 MHz)δ 8.62 (s, 1H), 7.76-7.82 (m, 2H), 7.65-7.67 (m, 1H), 7.43-7.52 (m, 2H),7.11 (dd, 1H), 6.35 (s, 1H), 3.69 (t, 4H). 2.85 (t, 4H), 2.29 (s, 3H).

Example 30: Preparation of1-(4-(3-(piperidin-4-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-(3-(piperidin-4-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

To a solution of 7-bromo-2-chloroquinoxaline (10 g, 41 mmol, 1 eq.) inCH₃OH (200 mL) was added K₂CO₃ (12.4 g, 91 mmol, 2 eq.). The resultingmixture was stirred under reflux for 2 h, then cooled to r.t. andconcentrated. The resulting residue was dissolved in THF (100 mL) andfiltered. The filtrate was concentrated to afford7-bromo-2-methoxyquinoxaline as a white solid (9.88 g, quant. yield).

To a solution of 7-bromo-2-methoxyquinoxaline (26.7 g, 0.11 mol, 1.0eq.) in DMF (1100 mL) were added TEA (77.7 mL, 0.56 mol, 5.0 eq.),Et₃SiH (71.2 mL, 0.45 mol, 4.0 eq.) and Pd(dppf)Cl₂CH₂Cl₂ (4.56 g, 5.6mmol, 0.05 eq.). The resulting mixture was stirred at 90° C. in anautoclave for 12 h under CO (1 MPa), then cooled and concentrated. Theresulting residue was purified via flash column chromatography(EA/PE=1/4, v/v) to afford 3-methoxyquinoxaline-6-carbaldehyde as awhite solid (8.5 g, 40.5% yield).

To a solution of N-(4-bromophenyl)pivalamide (6.51 g, 25.5 mmol, 1.2eq.) in THF (300 mL) cooled at −78° C. was added n-BuLi (20.4 mL, 51.1mmol, 2.4 eq.) dropwise. The mixture was stirred at −78° C. for 30 min,then a solution of 3-methoxyquinoxaline-6-carbaldehyde (4.0 g, 21.5mmol, 1.0 eq.) in THF (200 mL) was added dropwise. The mixture wasstirred at −78° C. for 1 h, then quenched by the addition of aqueousNH₄Cl solution. The mixture was extracted with EA (50 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The resulting residue was purified via flash columnchromagraphy (PE/EA=3/1, v/v) to affordN-(4-(hydroxy(3-methoxyquinoxalin-6-yl)methyl)phenyl)pivalamide (1.45 g,18.7% yield).

To a solution ofN-(4-(hydroxy(3-methoxyquinoxalin-6-yl)methyl)phenyl)pivalamide (1.45 g,3.97 mmol, 1.0 eq.) in DCM (50 mL) was added MnO₂ (1.7 g, 19.9 mmol, 5.0eq.). The resulting mixture was stirred at 50° C. overnight, then cooledand filtered. The filtrate was concentrated and the resulting residuewas purified via flash column chromatography (PE/EA=3/1, v/v) to affordN-(4-(3-methoxyquinoxaline-6-carbonyl)phenyl)pivalamide (410 mg, 28%yield).

To a solution of N-(4-(3-methoxyquinoxaline-6-carbonyl)phenyl)pivalamide(410 mg, 1.13 mmol) in MeOH (20 mL) was added 25% HCl (5 mL) at 0° C.dropwise. The mixture was then stirred r.t. overnight, then concentratedto provide crudeN-(4-(3-hydroxyquinoxaline-6-carbonyl)phenyl)pivalamide, which was usedin the next step without further purification.

A solution of N-(4-(3-hydroxyquinoxaline-6-carbonyl)phenyl)pivalamide(394 mg, 1.13 mmol) in SOCl₂(30 mL) was heated under reflux overnight,then cooled and concentrated. The resulting residue was purified viaflash column chromatography (PE/EA=4/1, v/v) to affordN-(4-(3-chloroquinoxaline-6-carbonyl)phenyl)pivalamide (60 mg, 14.5%yield).

A mixture of N-(4-(3-chloroquinoxaline-6-carbonyl)phenyl)pivalamide (60mg, 0.16 mmol, 1.0 eq.), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(60.5 mg, 0.20 mmol, 1.2 eq.), Pd(PPh₃)₄(9.2 mg, 0.008 mmol, 0.05 eq.)and Na₂CO₃ (68 mg, 0.64 mmol, 4.0 eq.) in CH₃CN and water (8 mL/8 mL)was heated at 60° C. under N₂ protection overnight, then cooled andconcentrated. The resulting residue was purified via flash columnchromatography (PE/EA=2/1, v/v) to provide tert-butyl4-(7-(4-pivalamidobenzoyl)quinoxalin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(61 mg, 84% yield).

To a solution of tert-butyl4-(7-(4-pivalamidobenzoyl)quinoxalin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(103 mg, 0.2 mmol, 1.0 eq.) in MeOH/THF (20 mL/20 mL) was added 10% Pd/C(10 mg) under H₂ atmosphere (1 atm). The resulting mixture was stirredat r.t. overnight, then filtered. The filtrate was concentrated toprovide crude tert-butyl4-(7-(hydroxy(4-pivalamidophenyl)methyl)quinoxalin-2-yl)piperidine-1-carboxylate(98 mg, 94.8% yield), which was used in the next step without furtherpurification.

To a solution of tert-butyl4-(7-(hydroxy(4-pivalamidophenyl)methyl)quinoxalin-2-yl)piperidine-1-carboxylate(98 mg, 0.19 mmol, 1.0 eq.) in DCM (15 mL) was added MnO₂ (82 mg, 0.94mmol, 5.0 eq.). The resulting mixture was stirred at 50° C. overnight,then cooled, filtered and concentrated to afford tert-butyl4-(7-(4-pivalamidobenzoyl)quinoxalin-2-yl)piperidine-1-carboxylate (97mg, quant. yield), which was used in the next step without furtherpurification.

To a solution of tert-butyl4-(7-(4-pivalamidobenzoyl)quinoxalin-2-yl)piperidine-1-carboxylate (97mg, 0.19 mmol, 1.0 eq.) in HOAc (3 mL) was added cone. HCl (1.5 mL). Themixture was stirred at 110° C. for 4 h, then cooled and concentrated togive crude (4-aminophenyl)(3-(piperidin-4-yl)quinoxalin-6-yl)methanonewhich was used in the next step without further purification.

To a solution of(4-aminophenyl)(3-(piperidin-4-yl)quinoxalin-6-yl)methanone (62 mg, 0.19mmol, 1.0 eq.) in MeOH (15 mL) were added (Boc)₂O (49 mg, 0.23 mmol, 1.2eq.) and TEA (57 mg, 0.56 mmol, 3.0 eq.). The resulting mixture wasstirred at r.t. for 1 h, then concentrated. The resulting residue waspurified via flash column chromatography (PE/EA=1/1, v/v) to affordtert-butyl 4-(7-(4-aminobenzoyl)quinoxalin-2-yl)piperidine-1-carboxylate(72.1 mg, 89% yield).

A mixture of tert-butyl4-(7-(4-aminobenzoyl)quinoxalin-2-yl)piperidine-1-carboxylate (36 mg,0.083 mmol, 1.0 eq.), DMAP (21 mg, 0.17 mmol, 2.0 eq.) and1-isocyanato-3-(trifluoromethyl)benzene (47 mg, 0.25 mmol, 3.0 eq.) inTHF (10 mL) were heated at 70° C. for 3 h, then cooled and concentrated.The resulting residue was purified via flash column chromatography(PE/EA=2/1, v/v) to afford tert-butyl4-(7-(4-(3-(3-(trifluoromethyl)phenyl)ureido)benzoyl)quinoxalin-2-yl)piperidine-1-carboxylate(32 mg, 62% yield).

To a solution of tert-butyl4-(7-(4-(3-(3-(trifluoromethyl)phenyl)ureido)benzoyl)quinoxalin-2-yl)piperidine-1-carboxylate (32 mg, 0.052 mmol, 1.0 eq.) inDCM (1 mL) was added TFA (1 mL). The resulting mixture was stirred atr.t. for 1 h, then concentrated. The resulting residue was basified topH=7-8 by the addition of sat.NaHCO₃ solution and extracted with DCM (20mL×2). The combined organic layers were dried over Na₂SO₄ andconcentrated to afford1-(4-(3-(piperidin-4-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(26.8 mg, 99% yield). LRMS (M+H⁺) m/z calculated 520.2, found 520.2. ¹HNMR (DMSO-d6, 400 MHz) δ 9.79 (s, 1H), 9.69 (s, 1H), 9.06 (s, 1H),8.21-8.23 (m, 2H), 8.06-8.09 (m, 2H), 7.52-7.85 (m, 6H), 7.34 (d, 1H),3.15-3.24 (m, 3H), 2.75 (t, 2H), 1.79-1.99 (m, 4H), 1.17-1.23 (m, 1H).

Example 31: Preparation of1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperidin-4-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperidin-4-yl)quinoxaline-6-carbonyl)phenyl)urea

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-(4-(3-(piperidin-4-yl)quinoxaline-6-carbonyl)phenyl)urea(31.5 mg) was prepared as described for1-(4-(3-(piperidin-4-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea.LRMS (M+H⁺) m/z calculated 538.2, found 538.2. ¹H NMR (CDCl₃, 400 MHz) δ8.84 (s, 1H), 8.03-8.31 (m, 5H), 7.78 (d, 2H), 7.48-7.56 (m, 4H), 7.04(t, 1H), 3.27 (d, 2H), 3.12 (t, 1H), 2.84 (t, 2H), 2.42 (s, 1H),1.86-2.06 (m, 4H).

Example 32: Preparation of1-(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea

A mixture of 7-bromo-2-chloroquinoxaline (9.7 g, 40 mmol, 1.0 eq.),potassium vinyltrifluoroborate (6.43 g, 48 mmol, 1.2 eq.),Pd(dppf)Cl₂.CH₂Cl₂ (1.63 g, 2 mmol, 0.05 eq.) and TEA (8.1 g, 80 mmol,2.0 eq.) in dioxane (150 mL) under N₂ were heated at 80° C. for 5 h,then cooled and poured into water (150 mL). The mixture was thenextracted with EA (150 mL×3) and the combined organic layers were washedwith water, dried over Na₂SO₄, filtered and concentrated below 25° C. togive crude 7-bromo-2-vinylquinoxaline which was used in the next stepwithout further purification.

To a solution of 7-bromo-2-vinylquinoxaline (11.5 g, 40 mmol, 1.0 eq.)in THF and H₂O (220 mL/70 mL) was added catalytic amount of OsO₄. Themixture was then cooled to 0° C. and was added NaIO₄ (21.4 g, 100 mmol,2.5 eq.) in water (150 mL). The resulting mixture was stirred at r.t.for 4.5 h, then extracted with EA (150 mL×3). The combined organiclayers were washed with brine (150 mL), dried over Na₂SO₄, filtered andconcentrated. The resulting residue was purified via flash columnchromagraphy (PE/EA=20/1, v/v) to afford7-bromoquinoxaline-2-carbaldehyde (2.7 g, 28% yield for two step).

To a solution of 7-bromoquinoxaline-2-carbaldehyde (800 mg, 3.37 mmol,1.0 eq.) in THF (8 mL) were added NH₃. H₂O (12 mL) at r.t., followed byI₂ (1.03 g, 4.05 mmol, 1.2 eq.). The resulting mixture was stirred atr.t. for 2 h, then quenched by the addition of aqueous NaHSO₃ solution.The mixture was extracted with EA (20 mL×3). The combined organic layerswere washed with brine (15 mL), dried over Na₂SO₄, filtered andconcentrated. The resulting residue was purified via flash columnchromagraphy (PE/EA=20/1, v/v) to afford7-bromoquinoxaline-2-carbonitrile (332 mg, 42% yield).

To a solution of 4-bromo-3-fluoroaniline (19 g, 0.1 mol, 1 eq.) indioxane (150 mL) and H₂O (150 mL) was added NaHCO₃ (33.6 g, 0.4 mmol, 1eq.) and (Boc)₂O (43.2 g, 0.2 mol). The resulting mixture was stirred atr.t. overnight, then evaporated. The water phase was extracted with EA(100 mL×3). The combined organic layers were dried over Na₂SO₄,filtered, concentrated. The resulting residue was purified via flashcolumn (PE/EA=50/1, v/v) to afford tert-butyl(4-bromo-3-fluorophenyl)carbamate (18 g, 62.5%).

A mixture of tert-butyl (4-bromo-3-fluorophenyl)carbamate (9.62 g, 33.16mmol, 1.0 eq.),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (12.63 g,49.47 mmol, 1.5 eq.), Pd(dppf)Cl₂.CH₂Cl₂ (2.71 g, 3.32 mmol, 0.1 eq.),KOAc (9.76 g, 99.48 mmol, 3.0 eq.) in DMSO/dioxane (3 mL/150 mL) washeated to 95° C. under N₂ overnight, then cooled and filtered. Thefiltrate was concentrated and the residue was purified via flash columnchromatography (PE/EA=20/1, v/v) to afford tert-butyl(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate(10.5 g, 94% yield).

To a solution of tert-butyl(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate(9.0 g, 18.6 mmol, 1.0 eq.) in acetone (200 mL) was added a solution ofNH₄OAc (8.6 g, 111.6 mmol, 6.0 eq.) in water (100 mL). The mixture wascooled to 0° C. and added NaIO₄ (23.87 g, 111.6 mmol, 6.0 eq.). Theresulting mixture was stirred at r.t. overnight, then concentrated,diluted with water (50 mL), acidified to pH=1-2 with 1N HCl at 0° C.,then extracted with EA (150 mL×3). The combined organic layers werewashed with brine (50 mL), dried over Na₂SO₄, filtered and concentratedto afford crude (4-((tert-butoxycarbonyl)amino)-2-fluorophenyl)boronicacid (4.2 g, 89% yield).

A mixture of 7-bromoquinoxaline-2-carbonitrile (400 mg, 1.71 mmol, 1.0eq.), (4-((tert-butoxycarbonyl)amino)-2-fluorophenyl)boronic acid (654mg, 2.56 mmol, 1.5 eq.), Pd(OAc)₂ (58 mg, 0.257 mmol, 0.15 eq.), PAd₂Bu(276 mg, 0.77 mmol, 0.45 eq.), and TMEDA (199 mg, 1.71 mmol, 1.0 eq.) intoluene (20 mL) was heated at 97° C. under N₂ overnight, then cooled andfiltered. The filtrate was concentrated and the residue was purified viaflash column chromatography (PE/EA=10/1, v/v) to afford tert-butyl(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)carbamate (330 mg, 49%yield).

To a solution of tert-butyl(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)carbamate (180 mg,0.46 mmol, 1.0 eq.) in DCM (12 mL) was added TFA (4 mL). The resultingmixture was stirred at r.t. for 1 h, then concentrated. The resultingresidue was basified to pH 7-8 by the addition sat.NaHCO₃ solution andextracted with DCM (20 mL×3). The combined organic layers were driedover Na₂SO₄ and concentrated to afford cude7-(4-amino-2-fluorobenzoyl)quinoxaline-2-carbonitrile (134 mg, 99%yield).

A mixture of 7-(4-amino-2-fluorobenzoyl)quinoxaline-2-carbonitrile (67mg, 0.23 mmol, 1.0 eq.) and 1-isocyanato-3-(trifluoromethyl)benzene (47mg, 0.25 mmol, 1.1 eq.) in pyridine (3 mL) were heated at 100° C. for 1h, then cooled and concentrated. The resulting residue was purified viaflash column chromatography (PE/EA=2/1, v/v) to afford1-(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea(81 mg, 74% yield). LRMS (M+H⁺) m/z calculated 480.1, found 480.1. ¹HNMR (DMSO-d6, 400 MHz). δ 9.52 (s, 1H), 9.48 (s, 1H), 9.29 (s, 1H), 8.43(d, 1H), 8.35 (s, 2H), 8.02 (d, 1H), 7.62-7.75 (m, 3H), 7.55-7.58 (m,1H), 7.38 (dd, 2H).

Example 33: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)urea(19.6 mg) was prepared as described for1-(4-(3-cyanoquinoxaline-6-carbonyl)-3-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea.LRMS (M+^(H)) m/z calculated 512.1, found 512.1. ¹H NMR. (DMSO-d6, 400MHz) δ 9.58 (s, 1H), 9.48 (s, 1H), 9.41 (s, 1H), 8.43 (s, 1H), 8.35 (s,2H), 8.11 (d, 1H), 7.64-7.72 (m, 4H), 7.39 (d, 1H).

Example 34: Preparation of3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide

3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide

To a solution of tert-butyl4-(7-(4-amino-2-fluorobenzoyl)quinoxalin-2-yl)piperazine-1-carboxylate(60 mg, 0.13 mmol, 1.0 eq.) in pyridine (1.5 mL) was added3-fluorobenzoyl chloride (31.6 mg, 0.20 mmol, 1.5 eq.). The resultingmixture was stirred at r.t. for 1 h, then concentrated. The resultingresidue was washed with sat.Na₂CO₃, extracted with EA (20 mL×2), andwashed with water. The combined organic layers were dried over Na₂SO₄and concentrated to afford cude tert-butyl4-(7-(2-fluoro-4-(3-fluorobenzamido)benzoyl)quinoxalin-2-yl)piperazine-1-carboxylate,which was used for the next step without further purification.

To a solution of tert-butyl4-(7-(2-fluoro-4-(3-fluorobenzamido)benzoyl)quinoxalin-2-yl)piperazine-1-carboxylate(60 mg, 0.10 mmol, 1.0 eq.) in DCM (1 mL) was added TFA (1 mL). Theresulting mixture was stirred at r.t. for 1 h, then concentrated. Theresulting residue was basified to pH=7-8 by the addition sat.NaHCO₃solution, extracted with EA (20 mL×2), dried over Na₂SO₄ andconcentrated. The resulting residue was purified via prep-TLC(DCM/MeOH=9/1, v/v) to afford3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide(30.7 mg, 49.8% yield, two step). LRMS (M+H⁺) m/z calculated 474.2,found 474.2. ¹H NMR (CD₃OD, 300 MHz). δ 8.83 (s, 1H), 8.39 (s, 1H), 8.19(d, 1H), 7.63-7.99 (m, 8H), 3.99-4.03 (m, 4H), 3.23-3.27 (m, 4H).

Example 35: Preparation of4-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide

4-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide

4-Chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide(39.1 mg) was prepared as described for3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide.LRMS (M+H⁺) m/z calculated 490.1, found 490.1. ¹H NMR (CD₃OD, 300 MHz).δ 8.85 (s, 1H), 7.55-8.00 (m, 10H), 4.02-4.05 (m, 4H), 3.26-3.33 (m,4H).

Example 36: Preparation of3-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide

3-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide

3-Chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide(30.6 mg) was prepared as described for3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide.LRMS (M+H⁺) m/z calculated 490.1, found 490.2. ¹H NMR (CD₃OD, 300 MHz).δ 8.87 (s, 1H), 7.88-8.03 (m, 6H), 7.56-7.68 (m, 4H), 4.02-4.05 (m, 4H),3.26-3.29 (m, 4H).

Example 37: Preparation ofN-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide

N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide

N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide(34.0 mg) was prepared as described for3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide.LRMS (M+H⁺) m/z calculated 524.2, found 524.2. ¹H NMR (CD₃OD, 300 MHz).δ 8.81 (s, 1H), 8.29-8.31 (m, 2H), 7.65-7.99 (m, 8H), 3.89-3.92 (m, 4H),3.08-3.11 (m, 4H).

Example 38: Preparation of4-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide

4-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide

4-chloro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide(31.6 mg) was prepared as described for3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide.LRMS (M+H⁺) m/z calculated 558.1, found 558.1. ¹H NMR (CD₃OD, 300 MHz).δ 8.83 (s, 1H), 8.39 (s, 1H), 8.19 (d, 1H), 7.79-7.99 (m, 5H), 7.63-7.66(m, 2H), 3.99-4.03 (m, 4H), 3.23-3.27 (m, 4H).

Example 39: Preparation of3-fluoro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide

3-fluoro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide

3-Fluoro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide(28 mg) was prepared as described for3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide.LRMS (M+H⁺) m/z calculated 475.2, found 475.2. ¹H NMR (DMSO-d6, 300MHz). δ 10.81 (s, 1H), 8.96 (s, 1H), 7.74-8.00 (m, 10H), 3.72-3.77 (m,8H).

Example 40: Preparation of4-chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide

4-chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide

4-Chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide(62.8 mg) was prepared as described for3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide.LRMS (M+H⁺) m/z calculated 475.2, found 475.2. ¹H NMR (DMSO-d6, 300MHz). δ 10.82 (s, 1H), 8.95 (s, 1H), 7.64-8.03 (m, 10H), 3.72-3.78 (m,8H).

Example 41: Preparation of4-chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide

4-chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide

4-Chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide(42.1 mg) was prepared as described for3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide.LRMS (M+H⁺) m/z calculated 559.1, found 559.1. ¹H NMR (DMSO-d6, 300MHz). δ 11.00 (s, 1H), 8.96 (s, 1H), 8.41 (s, 1H), 8.28 (d, 1H),7.71-7.99 (m, 7H), 3.71-3.79 (m, 8H).

Example 42: Preparation of3-chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide

3-chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide

3-Chloro-N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzamide(40.5 mg) was prepared as described for3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide.LRMS (M+^(H)) m/z calculated 491.1, found 491.1. ¹H NMR (DMSO-d6, 300MHz). δ 10.84 (s, 1H), 8.94 (s, 1H), 7.61-8.04 (m, 10H), 3.75 (m, 8H).

Example 43: Preparation ofN-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide

N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide

N-(3-fluoro-4-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide(36 mg) was prepared as described for3-fluoro-N-(3-fluoro-4-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzamide.LRMS (M+H⁺) m/z calculated 525.1, found 525.1. ¹H NMR (DMSO-d6, 300MHz). δ 10.96 (s, 1H), 8.95 (s, 1H), 7.97-8.00 (m, 2H), 7.73-7.84 (m,8H), 3.75 (m, 8H).

Example 44: Inhibitory Activity Against Kinases BRAF and BRAF V600E

Inhibitory activities Inhibitory activities of compounds against BRAF,and BRAF V600E were measured by Invitrogen using Z′-LYTE® Method asbriefly described in the following. 4× Test compounds are dissolved in1% DMSO. Kinase reaction mixture consists of 0.09-0.34 ng B-Raf (or0.002-0.006 ng BRAF V600E), 1× inactive MAP2K1 (MEK1)/inactive MAPK1(ERK2), and 2 μM Ser/Thr 03 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mMMgCl2, 1 mM EGTA. ATP solutions are diluted to a 4×ATP workingconcentration in Kinase Buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mMMgCl2, 1 mM EGTA). Reaction started by 30-second shaking of mixtureconsisting of 2.5 μL 4× test compound, 2.5 μL 2× kinase reaction mixtureand 2.5 μL 4×ATP Solution on Bar-coded Corning, low volume NBS, black384-well plate (Corning Cat. #3676). Then the mixture was incubated for60-minute at room temperature for the kinase reaction, followed byaddition of 5 μL of a 1:1024 dilution of development reagent A and30-second plate shake. The mixture was then incubated for another60-minute at room temperature for development reaction. Fluorescence wasread by plate reader. IC₅₀ was calculated by plotting the concentrationof compound vs the percentage of inhibition in treated wells usingGraphPad Prism 5.

Table 2 and 3 show % inhibition at 1 μM of several compounds of theinvention against BRAF and BRAF V600E, respectively, using Z′-LYTE®method. The scale utilized in Tables 2 and 3 is as follows: +++ morethan 89% inhibition; ++ between 70% and 89% inhibition; and + less than70% inhibition.

TABLE 2 Biological activity of several illustrative compounds againstBRAF Inhibition Compounds ++ C09, C11 + C02, C28, C01, C12, C13, C04,C14, C21, C03, C05, C20, C26, C10, C16, C19, C17

TABLE 3 Biological activity of several illustrative compounds againstBRAF V600E Inhibition Compounds +++ C33, C13, C01, C16, C17, C20, C14,C21, C09, C10, C26, C19, C11 ++ C18, C31, C23, C32, C27, C12, C28 + C30,C25, C29, C04, C07, C08, C06, C24, C03, C05, C15, C22, C02

Table 4 shows IC₅₀ values of several compounds of the invention againstBRAF V600E using Z′-LYTE® method. The scale utilized in Table 4 is asfollows: +++ less than 100 nM; and ++ greater than 100 nM.

TABLE 4 IC₅₀ of several illustrative compounds against BRAF V600E IC50Compounds +++ C17 ++ C14

Example 45: Inhibitory Activity Against Kinase KDR

Inhibitory activities of compounds against KDR (VEGFR2) were alsomeasured by Invitrogen using Z′-LYTE® Method as described above with thefollowing modification. The 2×KDR (VEGFR2)/Tyr 01 mixture is prepared in50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. The final 10μL Kinase Reaction consists of 0.5-11.7 ng KDR (VEGFR2) and 2 μM Tyr 01in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. After the1 hour Kinase Reaction incubation, 5 μL of a 1:256 dilution ofDevelopment Reagent B is added. Table 5 shows % inhibition at 1 μM ofseveral compounds of the invention using Z′-LYTE® method. The scaleutilized in Table 5 is as follows: +++ more than 89% inhibition; ++between 70% and 89% inhibition; and + less than 70% inhibition.

TABLE 5 Biological activity of several illustrative compounds againstKDR Inhibition Compounds +++ C16, C14, C26, C21 ++ C06, C07, C15, C24,C18, C11, C12, C17 + C30, C29, C31, C02, C04, C08, C01, C05, C23, C28,C22, C32, C10, C27, C09, C13, C03, C25, C33, C20, C19

Table 6 shows IC50 values of several compounds of the invention againstKDR using Z′-LYTE® method. The scale utilized in Table 6 is as follows:+++ less than 100 nM; and ++ greater than 100 nM

TABLE 6 IC₅₀ of several illustrative compounds against KDR IC50Compounds +++ C17, C21, C26 ++ C11, C12, C14, C16

Example 46: Inhibition of Cancer Cell Growth by Compounds Using MTT orMTS Assay

Inhibition of cell growth by compounds was measured using MTT or MTSassay. Tumor cell lines were purchased from ATCC (American Type CultureCollection, Manassas, Va.). All cell lines were maintained in RPMI 1640(Hyclone) supplemented with 10% fetal bovine serum (FBS, Hyclone),glutamine (2 mM, Hyclone), and antibiotics (penicillin 100 U/mL andstreptomycin 50 μg/mL) at 37° C. in a humidified atmosphere of 5% CO₂ inair. Taxol (as a positive control, Sigma) and compounds were dissolvedin DMSO (Sigma), and the final concentration of DMSO in the medium was1%. Tumor cells were plated in 96-well plates at densities of about 2000(A375) or 4000 (A549 and Colo205) cells/well of a 96-well plate andallowed to adhere/grow for 24 h. They were then treated with variousconcentrations of drug and incubated for 72 h. For MTT method, mediumwas then removed by inverting and tapping the plates. 100 μL of MTT (0.5mg/ml) was added to each well followed by an incubated at 37° C. for 4h. MTT was then removed and 200 μL of DMSO was added to each well, andthe ODs at 570 nm were measured after a 5 second shaking cycle in a96-well spectrophotometer. For MTS method, 20 μL MTS (CellTiter 96Aqueous One Solution, Promega) was added to each well followed by anincubated at 37° C. for 2-4 h, solutions were then directly put in a96-well spectrophotometer, and the ODs at 490 nm were measured.

All concentrations of compounds were tested in triplicate and controlswere averaged over 4 wells. IC₅₀ was calculated by plotting theconcentration of compound vs the percentage of inhibition in treatedwells using GraphPad Prism 5. Data for representative compounds areshown below. Table 7 shows IC₅₀ values of several compounds of theinvention against A375 cells, Table 8 against A549 cells and Table 9against Colo205 cells. The scale utilized in Tables 7-9 is as follows:+++ less than 1000 nM; ++ between 1000 nM and 5000 nM; and + greaterthan 5000 nM. The scale utilized in

TABLE 7 IC₅₀ of several illustrative compounds in A375 cells IC₅₀Compounds +++ C8, C12, C14, C17, C21, C26, C16, C13, C41, C43 ++ C09,C11, C29, C02, C19, C01, C20, C18, C07, C10, C15, C06, C31, C28, C03,C33, C24, C42, C40, C39, C38 + C05, C27, C34, C35, C36, C37

TABLE 8 IC₅₀ of several illustrative compounds in A549 cells IC₅₀Compounds +++ C12, C14, C17, C21, C26 ++ C07, C08, C09, C06, C13, C11,C18, C03, C19, C10, C15, C04, C24, C29, C25, C02, C16 + C20, C30, C05,C22, C27, C01, C31, C23, C28

TABLE 9 IC₅₀ of several illustrative compounds in Colo205 cells IC₅₀Compounds +++ C11, C14 ++ C09, C12, C17, C21 + C01, C16

Example 47: Inhibition of Tumor Growth in Xenograft Model

Cells were implanted in BALB/c female nude mice and grown as tumorxenografts. When tumors achieved 150-250 mm³, mice were assigned intotreatment and control groups using randomized block design based upontheir tumor volumes. Each group contained 6 tumor-bearing mice. Tumorswere measured twice weekly in two dimensions using a caliper, and thetumor volume was calculated from two-dimensional measurements using theequation V=0.5×a×b² where a and b are the long and short diameters ofthe tumor, respectively. Relative tumor volume (RTV) was defined asTV_(t)/TV_(i), the ratio of the volume on a given day (TV_(t)) and thevolume at the start of treatment (TV_(i)). Relative tumor growth rate(T/C) was defined as RTV_(T)/RTV_(C), the ratio of relative tumor volumeof treatment group (RTV_(T)) and relative tumor volume of control group(RTV_(C)) on a given day. Inhibition of tumor growth in a Colo205 tumorxenograft model is shown below in Table 10 for compound C14.

TABLE 10 In vivo activity of an illustrative compound in Colo205 tumormodel Tumor Tumor Volume Volume Pre- Post- Dose treatment treatmentCompound (mg/kg) Schedule Route (mm3) (mm3) T/C Vehicle — qd X 21 i.p.234 1556 — C14 30 qd X 21 i.p. 233 1016 65%

While some embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. For example, for claimconstruction purposes, it is not intended that the claims set forthhereinafter be construed in any way narrower than the literal languagethereof, and it is thus not intended that exemplary embodiments from thespecification be read into the claims. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations on the scope of the claims.

1.-45. (canceled)
 46. A method of inhibiting KDR kinase activity in asubject, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, and R₁₀ are independently hydrogen, cyano, halo,hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, alkoxy,cycloalkyloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, alkyl,alkenyl, aryl, heteroaryl, heterocycloalkyl, amino, acyl,alkoxycarbonyl, aminocarbonyl, aminosulfonyl, carbamimidoyl, or alkynyl;R₉ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; R₁₁ is hydroxy, formyl, alkoxy, alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃,—C(NR₁₄)NR₁₂R₁₃, —C(NCN)NR₁₂R₁₃, or —SO₂NR₁₂R₁₃; or R₉ and R₁₁ may bejoined together with any intervening atoms to form a heterocycloalkylring; R₁₂ is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;R₁₃ and R₁₄ are independently hydrogen, alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; or R₁₂ and R₁₃ may be joinedtogether with any intervening atoms to form a heterocycloalkyl ring;wherein: any of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃,R₁₄, the heterocycloalkyl ring formed by R₉ and R₁₁, and theheterocycloalkyl ring formed by R₁₂ and R₁₃ may be substituted with oneor more substituents independently selected from the group consisting ofC₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₄alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo, —CO₂H,—C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl),—CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄alkylphenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl).
 47. The method of claim 46, wherein R₁ is hydrogen, cyano,halo, hydroxy, carboxy, optionally substituted alkoxy, optionallysubstituted aryloxy, optionally substituted alkoxycarbonyl, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocycloalkyl, optionallysubstituted amino, optionally substituted acyl, optionally substitutedalkoxycarbonyl, optionally substituted aminocarbonyl, optionallysubstituted aminosulfonyl, optionally substituted carbamimidoyl, oroptionally substituted alkynyl.
 48. The method of claim 46, wherein R₁is optionally substituted aryl, optionally substituted heterocycloalkyl,or optionally substituted heteroaryl.
 49. The method of claim 46,wherein R₁ is optionally substituted morpholinyl, optionally substitutedpiperazinyl, optionally substituted pyrrolidinyl, optionally substitutedpiperidinyl, optionally substituted imidazolyl, optionally substitutedpyrazolyl, or optionally substituted pyridyl.
 50. The method of claim46, wherein R₂, R₃, R₄, and R₅ are independently hydrogen, halo, cyano,optionally substituted alkoxy, or optionally substituted alkyl.
 51. Themethod of claim 46, wherein R₂, R₃, R₄, and R₅ are independentlyhydrogen or halo.
 52. The method of claim 46, wherein R₆, R₇, R₈, andR₁₀ are independently hydrogen, cyano, halo, optionally substitutedalkoxy, optionally substituted alkyl, optionally substituted acyl,optionally substituted alkoxycarbonyl, optionally substitutedaminocarbonyl, or optionally substituted aminosulfonyl.
 53. The methodof claim 46, wherein R₆, R₇, R₈, and R₁₀ are independently hydrogen,cyano, or halo.
 54. The method of claim 46, wherein R₉ is hydrogen,optionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl.
 55. The method of claim 46, whereinR₉ is hydrogen or optionally substituted lower alkyl.
 56. The method ofclaim 46, wherein R₁₁ is —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(NR₁₄)NR₁₂R₁₃,—C(NCN)NR₁₂R₁₃, or —SO₂NR₁₂R₁₃.
 57. The method of claim 46, wherein R₁₂is optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl; and R₁₃ and R₁₄, when present, areindependently hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, or optionally substituted heterocycloalkyl. 58.The method of claim 46, wherein R₁₂ is optionally substituted alkyl,optionally substituted aryl, or optionally substituted heteroaryl; andR₁₃ and R₁₄, when present, are independently hydrogen or optionallysubstituted alkyl.
 59. The method of claim 46, wherein R₁₂ is optionallysubstituted aryl.
 60. The method of claim 46, wherein R₁₂ is optionallysubstituted heteroaryl.
 61. The method of claim 46, wherein R₁₂ and R₁₃,when present, are joined together with any intervening atoms to form anoptionally substituted 4- to 8-membered heterocycloalkyl ring.
 62. Themethod of claim 46, wherein R₉ and R₁₁ are joined together with anyintervening atoms to form an optionally substituted 4- to 8-memberedheterocycloalkyl ring.
 63. The method of claim 46, wherein the subjectsuffers from a cancer selected from the group consisting of bladder,breast, colorectal, head and neck, liver, lung, skin, ovarian,pancreatic, prostate, renal, stomach, and thyroid cancer.
 64. The methodof claim 46, wherein the subject suffers from a cancer selected from thegroup consisting of melanoma, non-small cell lung cancer, colon cancer,thyroid cancer, and ovarian cancer.
 65. The method of claim 46, furthercomprising administering to the subject an additional anti-cancer and/orcytotoxic agent.